Substituted 4-aminocyclohexane derivatives

ABSTRACT

The invention relates to compounds that have an affinity to the μ-opioid receptor and the ORL 1-receptor, methods for their production, medications containing these compounds and the use of these compounds for the treatment of pain and other conditions.

This application is a continuation of U.S. patent application Ser. No.12/410,801, filed Mar. 25, 2009, now pending, which, in turn, claimspriority of European Patent Application No. 08005748.2, filed Mar. 27,2008, the entire contents of which patent applications are herebyincorporated herein by reference.

The invention relates to substituted cyclohexane derivatives that havean affinity to the μ-opioid receptor and the ORL 1-receptor, methods fortheir production, medications containing these compounds and the use ofthese compounds for the production of medications.

Cyclohexane derivatives that have an affinity to the μ-opioid receptorand the ORL 1-receptor are known in the prior art. In this context,reference can be made, for example, to the following documents in theirfull scope WO2002/090317, WO2002/90330, WO2003/008370, WO2003/008731,WO2003/080557, WO2004/043899, WO2004/043900, WO2004/043902,WO2004/043909, WO2004/043949, WO2004/043967, WO2005/063769,WO2005/066183, WO2005/110970, WO2005/110971, WO2005/110973,WO2005/110974, WO2005/110975, WO2005/110976, WO2005/110977,WO2006/018184, WO2006/108565, WO2007/079927, WO2007/079928,WO2007/079930, WO2007/079931, WO2007/124903, WO2008/009415 andWO2008/009416.

However, the known compounds are not satisfactory in every respect andthere is a need for further compounds with comparable or betterproperties.

Thus, in appropriate binding assays the known compounds occasionallyexhibit a certain affinity to the hERG ion channel, the L-type calciumion channel (phenylalkylamine, benzothiazepine, dihydropyridine bindingsites) or to the sodium channel in the BTX assay (batrachotoxin), whichcan be respectively interpreted as an indication of cardiovascularside-effects. Moreover, many of the known compounds exhibit only aslight solubility in aqueous media, which can adversely affect thebioavailability, inter alia. In addition, the chemical stability of theknown compounds is often merely inadequate. Thus, the compoundsoccasionally do not exhibit an adequate pH, UV or oxidation stability,which can adversely affect the storage stability and also the oralbioavailability, inter alia. Moreover, the known compounds have anunfavourable PK/PD (pharmacokinetic/pharmacodynamic) profile in someinstances, which can be displayed, for example, in too long a durationof effect.

The metabolic stability of the known compounds also appears to be inneed of improvement. An improved metabolic stability can point to anincreased bioavailability. A weak or absent interaction with transportermolecules that participate in the absorption and excretion of medicinalsubstances should be considered an indication of an improvedbioavailability and possibly low interactions of medications. Moreover,the interactions with the enzymes involved in the breakdown andexcretion of medicinal substances should also be as low as possible,since such test results also indicate that low interactions ofmedications or none at all are possibly to be expected.

Moreover, the known compounds at times exhibit only a low selectivitywith respect to the kappa-opioid receptor, which is responsible forside-effects such as e.g. dysphoria, sedation, diuresis. In addition,the known compounds at times exhibit a very high affinity to theμ-opioid receptor, which appears to be associated with otherside-effects, in particular respiratory depression, constipation andaddiction dependence.

WO 01/87838 discloses NK-1-receptor antagonists.

J. Med. Chem. 1996, 9, 911-920; J. Am. Chem. Soc. 1950, 72, 2411-2417;and Tetrahedron 2006, 62, 5536-5548 respectively disclose, inter alia,geminally substituted cyclohexyl-1,4-diamines, in which the amino groupsare, however, substituted with hydrogen atoms throughout.

DE 28 39 891 A1 discloses, inter alia,4-(dimethylamino)-1-methyl-4-p-tolyl cyclohexyl acetate.

The object forming the basis of the invention is to provide compoundsthat are suitable for pharmaceutical purposes and have advantages overthe compounds of the prior art.

This object is achieved by the compounds described hereinbelow.

It has been surprisingly found that substituted cyclohexane derivativescan be produced that have an affinity to the μ-opioid receptor and theORL 1-receptor.

The invention relates to compounds of the general formula (1),

wherein

Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ are respectively selectedindependently of one another from the group comprising —H, —F, —Cl, —Br,—I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀,—C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀,—OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; preferablyrespectively selected independently of one another from the groupcomprising —H, —F, —Cl, —CN and —C₁₋₈-aliphatic; or Y₁ and Y₁′, or Y₂and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ jointly stand for ═O;

Q stands for —R₀, —C(═O)—R₀, —C(═O)OR₀, —C(═O)NHR₀, —C(═O)N(R₀)₂ or—C(═NH)—R₀;

R₀ respectively independently stands for —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl,—C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic,—C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl;

R₁ and R₂, independently of one another, stand for —H or —R₀; or R₁ andR₂ jointly form a ring and stand for —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₄CH₂CH₂—or —(CH₂)₃₋₆—; on condition that R₁ and R₂ preferably do not bothsimultaneously stand for —H;

R₃ stands for —R₀;

R₄ respectively independently stands for —H, —R₀ or —C(═O)R₀;

n stands for a whole number from 0 to 12, preferably for 0;

X stands for —O—, —S— or —NR_(A)—, preferably for —NR_(A)—;

R_(A) stands for —H, —R₀, —S(═O)₀₋₂R₀, —C(═O)R₀, —C(═O)OR₀, —C(═O)NH₂,—C(═O)NHR₀ or —C(═O)N(R₀)₂;

R_(B) stands for —H, —R₀, —C(═O)H, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀,—C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂—OR₀,—S(═O)₁₋₂—NH₂, —S(═O)₁₋₂—NHR₀ or —S(═O)₁₋₂—N(R₀)₂; or R_(A) and R_(B)jointly form a ring and stand for —(CH₂)₂₋₅—, —CH₂CH₂OCH₂CH₂— or—CH₂CH₂NR₄CH₂CH₂—; on condition that when X stands for —O— and at thesame time n stands for 0, R_(B) does not stand for —H;

wherein

“aliphatic” respectively is a branched or unbranched, saturated or amono- or polyunsaturated, unsubstituted or mono- or polysubstituted,aliphatic hydrocarbon residue;

“cycloaliphatic” respectively is a saturated or a mono- orpolyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic,mono- or multicyclic hydrocarbon residue, the number of ring-carbonatoms of which preferably lies in the specified range (i.e.“C₃₋₈-cycloaliphatic” preferably has 3, 4, 5, 6, 7 or 8 ring-carbonatoms);

wherein with respect to “aliphatic” and “cycloaliphatic”, “mono- orpolysubstituted” is understood to mean the mono- or polysubstitution,e.g. the mono-, di-, tri- or complete substitution, of one or morehydrogen atoms by substituents selected independently of one anotherfrom the group comprising aus —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O,—R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂; —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀,—NHC(═O)NH₂, —NHC(═O)—NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂;

“aryl”, respectively independently, stands for a carbocyclic ring systemwith at least one aromatic ring, but without heteroatoms in this ring,wherein, if necessary, the aryl residues can be condensed with furthersaturated, (partially) unsaturated or aromatic ring systems, and eacharyl residue can be present in unsubstituted or mono- or polysubstitutedform, wherein the aryl substituents can be the same or different and inany desired and possible position of the aryl;

“heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromatic residue,which contains 1, 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms, thesame or different, are nitrogen, oxygen or sulphur, and the heterocyclecan be unsubstituted or mono- or polysubstituted; wherein in the case ofthe substitution on the heterocycle the substituents can be the same ordifferent and can be in any desired and possible position of theheteroaryl; and wherein the heterocycle can also be part of a bi- orpolycyclic system;

wherein with respect to “aryl” and “heteroaryl”, “mono- orpolysubstituted” is understood to mean the mono- or polysubstitution ofone or more hydrogen atoms of the ring system by substituents selectedfrom the group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀,—C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)—N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,—OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NH—C(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃,—PO(OR₀)₂; wherein any N-ring atoms present can be respectively oxidised(N-oxide);

in the form of a single stereoisomer or mixture thereof, the freecompounds and/or their physiologically compatible salts and/or solvates,wherein 4-(dimethylamino)-1-methyl-4-p-tolyl cyclohexyl acetate and itssalts are preferably excepted.

In the combination of different residues, e.g. Y₁, Y₁′, Y₂, Y₂′, Y₃,Y₃′, Y₄ and Y₄′, and also the combination of residues at substituentsthereof such as e.g. —OR₀, —OC(═O)R₀, —OC(═O)NHR₀, a substituent, e.g.R₀, can assume different meanings within a substance for two or moreresidues, e.g. —OR₀, —OC(═O)R₀, —OC(═O)NHR₀.

The compounds according to the invention exhibit favourable binding tothe ORL 1-receptor and the μ-opioid receptor.

In a preferred embodiment, the compounds according to the invention havean affinity ratio of ORL 1/μ of at least 0.1. The ORL1/μ ratio isdefined as 1/[K_(i(ORL1))/K_(1(μ)]). It is particularly preferred if theORL 1/μ ratio amounts to at least 0.2 or at least 0.5, more preferred atleast 1.0 or at least 2.0, further preferred at least 3.0 or at least4.0, most preferred at least 5.0 or at least 7.5 and in particular atleast 10 or at least 15. In a preferred embodiment the ORL1/μ ratio liesin the range of 0.1 to 30, more preferred 0.1 to 25.

In another preferred embodiment, the compounds according to theinvention have an ORL1/μ affinity ratio of more than 30, more preferredat least 50, further preferred at least 100, most preferred at least 200and in particular at least 300.

The compounds according to the invention preferably have a K_(i) valueon the μ-opioid receptor of at maximum 500 nM, more preferred at maximum100 nM, further preferred at maximum 50 nM, most preferred at maximum 10nM and in particular at maximum 1.0 nM.

Methods for determining the K_(i) value on the μ-opioid receptor areknown to the person skilled in the art. The determination is preferablyconducted as described in association with the examples.

It has surprisingly been shown that compounds with affinity to the ORL1- and μ-opioid receptor, in which the ratio of ORL 1 to μ defined by1/[K_(i(ORL1))/K_(i(μ))] lies in the range of 0.1 to 30, preferably 0.1to 25, have a pharmacological profile that has significant advantagescompared to the other opioid receptor ligand:

-   1. The compounds according to the invention exhibit an efficacy in    acute pain models that is at times comparable with the usual stage-3    opioids. However, they are distinguished at the same time by a    significantly better compatibility compared to classic μ-opioids.-   2. In contrast to common stage-3 opioids, the compounds according to    the invention exhibit a significantly higher efficacy in mono- and    polyneuropathic pain models, which is attributable to a synergy of    ORL 1- and μ-opioid components.-   3. In contrast to common stage-3 opioids, the compounds according to    the invention exhibit in neuropathic animals a substantial,    preferably a complete, separation of antiallodynic or    antihyperalgesic effect and antinociceptive effect.-   4. In contrast to common stage-3 opioids, in animal models the    compounds according to the invention exhibit a significant increase    in efficacy for chronic inflammatory pain (carageenan- or    CFA-induced hyperalgesia, visceral inflammatory pain, amongst    others) compared to acute pain.-   5. In contrast to common stage-3 opioids, side-effects typical of    μ-opioids (respiratory depression, opioid-induced hyperalgesia,    physical dependence/withdrawal, psychic dependence/addiction, among    others) are significantly reduced or preferably not observed with    the compounds according to the invention in the therapeutically    effective dose range.

In view of the reduced μ-opioid side-effects, on the one hand, and theincreased efficacy in chronic, preferably neuropathic pain, on the otherhand, the mixed ORL 1/μ agonists are thus distinguished by significantlyincreased safety margins compared to pure μ-opioids. This results in asignificantly increased “therapeutic window” in the treatment of painconditions, preferably chronic pain, more preferred neuropathic pain.

It is preferred if Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ arerespectively selected independently of one another from the groupcomprising —H, —F, —Cl, —Br, —I, —CN, —NH₂, —NH—C₁₋₆-aliphatic,—NH—C₃₋₈-cycloaliphatic, —N(C₁₋₆-aliphatic)₂, —N(C₃₋₈-cycloaliphatic)₂,—N(C₁₋₆-aliphatic-OH)₂, —NO₂, —NH—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—NH—C₁₋₆-aliphatic-heteroaryl, —NH-aryl, —NH-heteroaryl, —SH,—S—C₁₋₆-aliphatic, —S—C₃₋₈-cycloaliphatic,—S—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —S—C₁₋₆-aliphatic-heteroaryl,—S-aryl, —S-heteroaryl, —OH, —O—C₁₋₆-aliphatic, —O—C₃₋₈-cycloaliphatic,—O—C₁₋₆-aliphatic-OH, —O—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—O—C₁₋₆-aliphatic-aryl, —O—C₁₋₆-aliphatic-heretoaryl, —O-aryl,—O-heteroaryl, —O—C(═O)C₁₋₆-aliphatic, —O—C(═O)C₃₋₄-cycloaliphatic,—O—C(═O)C₁₋₆-aliphatic-OH, —O—C(═O)C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—O—C(═O)C₁₋₆-aliphatic-aryl, —O—C(═O)C₁₋₆-aliphatic-heretoaryl,—O—C(═O)aryl, —O—C(═O)heteroaryl, —C₁₋₆-aliphatic, —C₃₋₈-cycloaliphatic,—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-aryl,—C₁₋₆-aliphatic-heteroaryl, -aryl, -heteroaryl, —C(═O)C₁₋₆-aliphatic,—C(═O)C₃₋₈-cycloaliphatic, —C(═O)C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—C(═O)C₁₋₆-aliphatic-aryl, —C(═O)C₁₋₆-aliphatic-heteroaryl, —C(═O)aryl,—C(═O)heteroaryl, —CO₂H, —CO₂—C₁₋₆-aliphatic, —CO₂—C₃₋₈-cycloaliphatic,—CO₂—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —CO₂—C₁₋₆-aliphatic-aryl,—CO₂—C₁₋₆-aliphatic-heteroaryl, —CO₂-aryl, —CO₂-heteroaryl; or Y₁ andY₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ jointly stand for ═O.It is preferred if Y₁, Y₁′, Y₂, Y₂′, Y³, Y³′, Y₄ and Y₄′ arerespectively selected independently of one another from the groupcomprising —H, —F, —Cl, —Br, —I, —CN, —NH₂ and —OH.

In a preferred embodiment one of the residues Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′,Y₄ and Y₄′ differs from —H and the remaining residues stand for —H.

It is particularly preferred if Y₁, Y₁′, Y², Y₂′, Y₃, Y₃′, Y₄ and Y₄′respectively stand for —H.

Q preferably stands for —R₀, —C(═O)R₀ or —C(═NH)R₀. It is particularlypreferred if Q stands for —C₁₋₈-aliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-deteroaryl, —C(═O)—C₁₋₈-aliphatic,—C(═O)-aryl, —C(═O)-heteroaryl, —C(═O)—C₁₋₈-aliphatic-aryl,—C(═O)—C₁₋₈-aliphatic-heteroaryl, —C(═NH)—C₁₋₈-aliphatic, —C(═NH)-aryl,—C(═NH)-heteroaryl, —C(═NH)—C₁₋₈-aliphatic-aryl, or—C(═NH)—C₁₋₈-aliphatic-heteroaryl.

It is particularly preferred if Q stands for —C₁₋₈-aliphatic, -aryl,-heteroaryl, —C₁₋₈-aliphatic-aryl, —C(═O)-heteroaryl or—C(═NH)-heteroaryl.

In this case, -aryl and -heteroaryl can respectively be unsubstituted ormono- or polysubstituted, preferably with substituents that are selectedindependently of one another from the group comprising —C₁₋₈-aliphatic,—OH, —OC₁₋₈-aliphatic, —C₁₋₈-aliphatic-O—C₁₋₈-aliphatic (e.g.—CH₂—O—CH₃), —CF₃, —F, —Cl, —Br, —NO₂, —CN, -heteroaryl,—C₁₋₈-aliphatic-aryl and —C₁₋₈-aliphatic-heteroaryl.

In a preferred embodiment Q is selected from the group comprising—C₁₋₈-alkyl, -phenyl, -benzyl, -pyrrolyl, -furyl, -thienyl, pyridyl,-indolyl, -benzofuryl and -benzothienyl, wherein these can respectivelybe unsubstituted or mono- or polysubstituted, preferably withsubstituents that are selected independently of one another from thegroup comprising —C₁₋₈-aliphatic, —OH, —OC₁₋₈-aliphatic,—C₁₋₈-aliphatic-O—C₁₋₈-aliphatic, —CF₃, —F, —Cl, —Br, —NO₂, —CN,-heteroaryl, —C₁₋₈-aliphatic-aryl and —C₁₋₈-aliphatic-heteroaryl (e.g.-ethyl-4-pyridyl). It is particularly preferred if Q is selected fromthe group comprising:

R₀, respectively independently, preferably stands for —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl or—C₁₋₈-aliphatic-heteroaryl. In this case—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl or—C₁₋₈-aliphatic-heteroaryl mean that the residues —C₃₋₁₂-cycloaliphatic,-aryl or -heteroaryl are respectively bonded via a bivalent bridge—C₁₋₈-aliphatic-. Preferred examples of —C₁₋₈-aliphatic-aryl are—CH₂—C₆H₅, —CH₂CH₂—C₆H₅, and —CH═CH—C₆H₅.

R₁ and R₂, independently of one another, preferably stand for —H;—C₁₋₆-aliphatic; —C₃₋₈-cyclo-aliphatic, —C₁₋₆-aliphatic-aryl,—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic or —C₁₋₆-aliphatic-heteroaryl; orthe residues R₁ and R₂ together form a ring and represent—CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₄CH₂CH₂— or —(CH₂)₃₋₆—, on condition that R₁and R₂ preferably do not both stand for —H at the same time. It is morepreferred if R₁ and R₂, independently of one another, stand for —H;—C₁₋₅-aliphatic; or the residues R₁ and R₂ together form a ring andrepresent —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₄—CH₂CH₂— or —(CH₂)₃₋₆—, wherein R₄preferably represents —H or —C₁₋₅-aliphatic, on condition that R₁ and R₂preferably do not both stand for —H at the same time. Particularlypreferred are those compounds, in which R₁ and R₂, independently of oneanother, stand for —CH₃ or —H, wherein R₁ and R₂ do not simultaneouslyrepresent —H; or R₁ and R₂ form a ring and represent —(CH₂)₃₋₄—.Compounds, in which R₁ and R₂ stand for —CH₃ or in which R₁ stands for—H and R₂ stands for —CH₃, are most particularly preferred.

It is particularly preferred if R₁ and R₂ together with the nitrogenatom, to which they are bonded, form one of the following functionalgroups:

R₃ preferably stands for —C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic, -aryl,-heteroaryl; or for -aryl, -heteroaryl or —C₃₋₈-cycloaliphaticrespectively bonded via a —C₁₋₃-aliphatic group.

It is particularly preferred if R₃ stands for -ethyl, -propyl, -butyl,-pentyl, -hexyl, -heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -benzyl,-naphthyl, -anthracenyl, -thiophenyl, -benzothio-phenyl, -furyl,-benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl,-pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinyl, respectivelyunsubstituted or mono- or polysubstituted; —C₅₋₆-cycloaliphatic,-phenyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothiophenyl,-pyridyl, -furyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl,-benzodioxanyl, -pyrrolyl, -pyrimidyl, -triazolyl or -pyrazinyl,respectively unsubstituted or mono- or polysubstituted, bonded via asaturated, unbranched —C₁₋₃-aliphatic group.

It is more preferred if R₃ stands for -propyl, -butyl, -pentyl, -hexyl,-phenyl, -furyl, -thiophenyl, -naphthyl, -benzyl, -benzofuranyl,-indolyl, -indanyl, -benzodioxanyl, -benzodioxolanyl, -pyridyl,-pyrimidyl, -pyrazinyl, -triazolyl or -benzothiophenyl, respectivelyunsubstituted or mono- or polysubstituted; -phenyl, -furyl or-thiophenyl, respectively unsubstituted or mono- or polysubstituted,bonded via a saturated, unbranched —C₁₋₃-aliphatic group.

It is further preferred if R₃ stands for -propyl, -butyl, -pentyl,-hexyl, -phenyl, -phenethyl, -thiophenyl, -pyridyl, -triazolyl,-benzothiophenyl or -benzyl, respectively substituted or unsubstituted,particularly preferred for -propyl, -3-methoxypropyl, -butyl, -pentyl,-hexyl, -phenyl, -3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl,-thienyl, -benzothiophenyl, -4-chlorobenzyl, -benzyl, -3-chlorobenzyl,-4-methylbenzyl, -2-chlorobenzyl, -4-fluorobenzyl, -3-methylbenzyl,-2-methylbenzyl, -3-fluorobenzyl, -2-fluorobenzyl,-1-methyl-1,2,4-triazolyl or -phenethyl.

It is especially preferred if R₃ stands for -butyl, -ethyl,-3-methoxypropyl, -benzothiophenyl, -phenyl, -3-methylphenyl,-3-fluorophenyl, -benzo[1,3]-dioxolyl, -benzyl,-1-methyl-1,2,4-triazolyl, -thienyl or -phenethyl.

It is most preferred if R₃ stands for -phenyl, -benzyl or -phenethyl,respectively unsubstituted or mono- or polysubstituted on the ring;—C₁₋₅-aliphatic, —C₄₋₆-cycloaliphatic, -pyridyl, -thienyl, -thiazolyl,-imidazolyl, -1,2,4 triazolyl or -benzimidazolyl, unsubstituted or mono-or polysubstituted.

It is particularly preferred if R₃ stands for -phenyl, -benzyl,-phenethyl, -thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4triazolyl, -benzimidazolyl or -benzyl, unsubstituted or mono- orpolysubstituted with —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH,—CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂; ethyl, -n-propyl, -2-propyl,-allyl, -n-butyl, -iso-butyl, -sec-butyl, -tert-butyl, -n-pentyl,-iso-pentyl, -neo-pentyl, -n-hexyl, -cyclopentyl or -cyclohexyl,respectively unsubstituted or mono- or polysubstituiert with —OH, —OCH₃or —OC₂H₅, wherein -thienyl, -pyridyl, -thiazolyl, -imidazolyl,-1,2,4-triazolyl and -benzimidazolyl are preferably unsubstituted.

It is particularly preferred if R₃ stands for -phenyl, unsubstituted ormono-substituted with —F, —Cl, —CN, —CH₃; -thienyl; -ethyl, -n-propyl or-n-butyl, unsubstituted or mono- or polysubstituted with —OCH₃, —OH or—OC₂H₅, in particular with —OCH₃.

R₄ preferably stands for —H, —C₁₋₅-aliphatic, —C₃₋₈-cycloaliphatic,-aryl, -heteroaryl, —C₁₋₆-aliphatic-aryl,—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-heteroaryl,—C(═O)aryl, —C(═O)heteroaryl, or —C(═O)C₁₋₆-aliphatic, more preferredfor —H or —C₁₋₅-aliphatic.

It is preferred if n stands for a whole number from 0 to 6, morepreferred for 0, 1, 2 or 3, further preferred for 0 or 1, particularlypreferred if n=0.

R_(B) preferably stands for —H, —C₁₋₆-aliphatic, —C₃₋₈-cycloaliphatic,aliphatic, —C₁₋₆-aliphatic-aryl, —C₁₋₆-aliphatic-heteroaryl, -aryl,-heteroaryl, —C(═O)H, —C(═O)C₁₋₆-aliphatic , —C(═O)C₃₋₈-cycloaliphatic,—C(═O)C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C(═O)C₁₋₆-aliphatic-aryl,—C(═O)C₁₋₆-aliphatic-heteroaryl, —C(═O)—C₃₋₈-cycloaliphatic-aryl,—C(═O)—C₃₋₈-cycloaliphatic-heteroaryl, —C(═O)aryl, —C(═O)heteroaryl,—C(═O)OH, —CO₂—C₁₋₆-aliphatic, —CO₂—C₃₋₈-cycloaliphatic,—CO₂—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, aliphatic-aryl,—CO₂—C₁₋₆-aliphatic-heteroaryl, —CO₂-aryl, —CO₂-heteroaryl, —C(═O)NH₂,—C(═O)NHC₁₋₆-aliphatic, —C(═O)NHC₃₋₈-cycloaliphatic,—C(═O)NHC₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C(═O)NHC₁₋₆-aliphatic-aryl,—C(═O)NHC₁₋₆-aliphatic-heteroaryl, —C(═O)NH aryl, —C(═O)NH heteroaryl,—C(═O)N(C₁₋₆-aliphatic)₂, —C(═O)N(C₃₋₈-cycloaliphatic)₂,—C(═O)N(C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic)₂,—C(═O)N(C₁₋₆-aliphatic-aryl)₂, —C(═O)N(C₁₋₆-aliphatic-heteroaryl)₂,—C(═O)N(aryl)₂, —C(═O)N(heteroaryl)₂, —S(═O)₁₋₂—C₁₋₆-aliphatic,—S(═O)₁₋₂—C₃₋₈-cycloaliphatic,—S(═O)₁₋₂—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—S(═O)₁₋₂—C₁₋₆-aliphatic-aryl, —S(═O)₁₋₂—C₁₋₆-aliphatic-heteroaryl,—S(═O)₁₋₂—C₃₋₈-cycloaliphatic-aryl,—S(═O)₁₋₂—C₃₋₈-cycloaliphatic-heteroaryl —S(═O)₁₋₂-aryl,—S(═O)₁₋₂-heteroaryl, —S(═O)₁₋₂—OC₁₋₆-aliphatic,—S(═O)₁₋₂—OC₃₋₈-cycloaliphatic,—S(═O)₁₋₂—OC₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—S(═O)₁₋₂—OC₁₋₆-aliphatic-aryl, —S(═O)₁₋₂—OC₁₋₆-aliphatic-heteroaryl,—S(═O)₁₋₂—O aryl, —S(═O)₁₋₂—O heteroaryl, —S(═O)₁₋₂—NH₂,—S(═O)₁₋₂—NHC₁₋₆-aliphatic, —S(═O)₁₋₂—NHC₃₋₈-cycloaliphaic,—S(═O)₁₋₂—NHC₁₋₆-aliphatic-C₃₋₈-cycloaliphatic,—S(═O)₁₋₂—NHC₁₋₆-aliphatic-aryl, —S(═O)₁₋₂—NHC₁₋₆-aliphatic-heteroaryl,—S(═O)₁₋₂—NH-aryl, —S(═O)₁₋₂—NH-heteroaryl,—S(═O)₁₋₂—N(C₁₋₆-aliphatic)₂, —S(═O)₁₋₂—N(C₃₋₈-cycloaliphatic)₂,—S(═O)₁₋₂—N(C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic)₂,—S(═O)₁₋₂—N(C₁₋₆-aliphatic-aryl)₂,—S(═O)₁₋₂—N(C₁₋₆-aliphatic-heteroaryl)₂, —S(═O)₁₋₂—N(aryl)₂ or—S(═O)₁₋₂—N(heteroaryl)₂.

It is particularly preferred if R_(B) stands for —H, —C₁₋₈-aliphatic,—C₁₋₈-aliphatic-heteroaryl, —C(═O)—C₁₋₈-aliphatic,—C(═O)—C₁₋₈-aliphatic-aryl, —C(═O)—C₁₋₈-aliphatic-heteroaryl,—C(═O)—C₃₋₈-cycloaliphatic-aryl, —C(═O)—C₃₋₈-cycloaliphatic-heteroaryl,—C(═O)NH—C₁₋₈-aliphatic, —S(═O)₁₋₂—C₁₋₈-aliphatic, —S(═O)₁₋₂-aryl,—S(═O)₁₋₂-heteroaryl, —S(═O)₁₋₂—C₁₋₈-aliphatic-aryl,—S(═O)₁₋₂—C₁₋₈-aliphatic-heteroaryl, —S(═O)₁₋₂—C₃₋₈-cycloaliphatic-arylor —S(═O)₁₋₂—C₃₋₈-cycloaliphatic-heteroaryl.

X preferably stands for —O— or —NR_(A)—, particularly preferred for—NR_(A)—.

If X stands for —O—, then R_(B) preferably does not stand for —H. IfR_(B) stands for —H, then n is preferably 1, 2, 3 or 4. If X stands for—O—, then n preferably stands for 0 or 1 and R_(B) preferably stands for—C₁₋₈-aliphatic or —C₁₋₈-aliphatic-aryl.

If X stands for —NR_(A)—, then R_(A) stands for —H, —R₀, —S(═O)O₀₋₂R₀,—C(═O)R₀, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀ or —C(═O)N(R₀)₂; preferablyfor —H or —R₀ (in particular —C₁₋₈-aliphatic); particularly preferredfor —H or —CH₃; or R_(A) jointly with R_(B) forms a ring and stands for—(CH₂)₃₋₄—.

The group “R_(B)—X—(CH₂)_(n)—” preferably stands for

Preferred representatives of the group—(CH₂)_(n)—NH—C(═O)—C₁₋₈-aliphatic-aryl are illustrated below:

In a preferred embodiment of the compounds according to the inventionR_(A)=R_(B). In another preferred embodiment of the compounds accordingto the invention R_(A)≠R_(B).

In a particularly preferred embodiment of the compounds according to theinvention n=0 and X stands for —NR_(A)—. This then concerns geminallydi-substituted 1,4-diamines of the general formual (1.1)

wherein at least one of the two amino groups, preferably both aminogroups, cannot be simultaneously substituted with two hydrogen atoms.

For the purposes of the description hydrocarbon residues are dividedinto aliphatic hydrocarbon residues and aromatic hydrocarbon residues.

Aliphatic hydrocarbon residues are themselves divided into non-cyclicaliphatic hydrocarbon residues (=“aliphatic”) and cyclic aliphatichydrocarbon residues, i.e. alicyclic hydrocarbon residues(=“cycloaliphatic”). Cycloaliphatic compounds can be monocyclic ormulticyclic. Alicyclic hydrocarbon residues (“cycloaliphatic”) compriseboth pure aliphatic carbocycles and aliphatic heterocycles, i.e. —unlessexpressly specified-“cycloaliphatic” comprises pure aliphaticcarbocycles (e.g. cyclohexyl), pure aliphatic heterocycles (e.g.piperidyl or piperazyl) and also non-aromatic, multicyclic, possiblymixed, systems (e.g. decalinyl, decahydroquinolinyl).

Aromatic hydrocarbons are themselves divided into carbocyclic aromatichydrocarbons (=“aryl”) and heterocyclic aromatic hydrocarbons(=“heteroaryl”).

The classification of multicyclic, at least partially aromatic systemspreferably depends on whether at least one aromatic ring of themulticyclic system has at least one heteroatom (usually N, O or S) inthe ring. If at least one such heteroatom is present in this ring, thisis preferably a “heteroaryl” (even if a further carbocyclic aromatic ornon-aromatic ring with or without heteroatom is possibly present asadditionally present cycle of the multicyclic system); if such aheteroatom is not present in any of the possibly several aromatic ringsof the multicyclic system, then this is preferably “aryl” (even if aring heteroatom is present in a possibly additionally presentnon-aromatic cycle of the multicyclic system).

Therefore, the following priority in the classification applies withinthe cyclic substituents: heteroaryl>aryl>cycloaliphatic.

For the purposes of the description monovalent and multivalent, i.e.bivalent, hydrocarbon residues are not distinguished betweenconceptually, i.e. depending on the context, “C₁₋₃-aliphatic” coverse.g. —C₁₋₃-alkyl, —C₁₋₃-alkenyl and —C₁₋₃-alkinyl, as well as e.g.—C₁₋₃-alkylene-, —C₁₋₃-alkenylene- and C₁₋₃-alkinylene.

Aliphatic is preferably respectively a branched or unbranched, saturatedor a mono- or polyunsaturated, unsubstituted or mono- orpolysubstituted, aliphatic hydrocarbon residue. Where aliphatic is mono-or polysubstituted, the substituents are selected independently of oneanother from the group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O,—R₀, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂,—OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂,—SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂,—N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂,—NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂. Thus, “aliphatic”covers acyclic saturated or unsaturated hydrocarbon residues that can bebranched or straight-chain, i.e. alkanyls, alkenyls and alkinyls. Inthis case, alkenyls have at least one C═C double bond and alkinyls haveat least one C≡C triple bond. Preferred unsubstituted monovalentaliphatics comprise —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂CH₂—CH₂CH₃ and—CH₂CH₂CH₂CH₂CH₂CH₃; but also —CH═CH₂, —C≡CH, —CH₂CH═CH₂, —CH═CHCH₃,—CH₂C≡CH, —C≡CCH₃ and —CH═CHCH═CH₂. Preferred unsubstituted bivalentaliphatics comprise —CH₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH₂—,—CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)—CH₂—, —CH₂CH₂CH(CH₃)—,—CH—(CH₂CH₃)CH₂— and —CH₂CH₂—CH₂CH₂—; but also —CH═CH—, —C≡C—,—CH₂CH═CH—, —CH═CHCH₂—, —CH₂C≡C— and —C≡CCH₂—. Preferred substitutedmonovalent aliphatics comprise —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,—CH₂OH, —CH₂CH₂OH, —CH₂CHOHCH₃, —CH₂OCH₃ and —CH₂CH₂OCH₃. Preferredsubstituted bivalent aliphatics comprise —CF₂—, —CF₂CF₂—, —CH₂CHOH—,—CHOHCH₂— and —CH₂CHOHCH₂—. -Methyl-, -ethyl-, -n-propyl- and -n-butyl-are particularly preferred.

Cycloaliphatic is preferably respectively a saturated or a mono- orpolyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic(i.e. not aromatic), mono- or multicyclic hydrocarbon residue. Thenumber of ring-carbon atoms preferably lies in the specified range (i.e.a “C₃₋₈-cycloaliphatic” preferably has 3, 4, 5, 6, 7 or 8 ring-carbonatoms). For the purposes of the description “C₃₋₈-cycloaliphatic” ispreferably a cyclic hydrocarbon with 3, 4, 5, 6, 7 or 8 ring-carbonatoms, saturated or unsaturated, but not aromatic, wherein possibly oneor two carbon atoms are replaced independently of one another by aheteroatom S, N or O. Where cycloalkyl is mono- or polysubstituted, thesubstituents are selected independently of one another from the groupcomprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀,—C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀,—OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀,—SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃,—N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀,—NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂. Advantageously, C₃₋₈-cycloaliphaticis selected from the group comprising cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl, but alsotetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl,piperazinyl, pyrazolinonyl and pyrrolidinyl.

In association with “aliphatic” or “cycloaliphatic”, “mono- orpolysubstituted” is preferably understood to mean the mono- orpolysubstitution, e.g. the mono-, di-, tri- or 4-substitution, of one ormore hydrogen atoms by —F, —Cl, —Br, —I, —OH, —OC₁₋₆-alkyl,—OC(═O)C₁₋₆-alkyl, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C(═O)OC₁₋₆-alkyl or —C(═O)OH. Compounds, wherein “aliphaticsubstituted” or “cycloaliphatic substituted” means aliphatic orcycloaliphatic substituted with —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅,—NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂, are preferred.Particularly preferred substituents are —F, —Cl, —OH, —SH, —NH₂ and—C(═O)OH.

Polysubstituted residues are understood to be those residues that arepolysubstituted, e.g. twice or three times either at different or at thesame atoms, e.g. three times at the same C-atom, as in the case of —CF₃or —CH₂CF₃, or at different sites, as in the case of—CH(OH)—CH═CH—CHCl₂. The polysubstitution can occur with the same orwith different substituents. A substituent may also be substituteditself. Thus, —Oaliphatic also covers —OCH₂CH₂O—CH₂CH₂OH, amongstothers. It is preferred if aliphatic or cycloaliphatic is substitutedwith —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH,—OCH₃, —OC₂H₅ or —N(CH₃)₂. It is most particularly preferred ifaliphatic or cycloaliphatic is substituted with —OH, —OCH₃ or —OC₂H₅.

It is preferred if aryl respectively independently stands for acarbocyclic ring system with at least one aromatic ring, but withoutheteroatoms in this ring, wherein the aryl residues can possibly becondensed with further saturated, (partially) unsaturated or aromaticring systems and each aryl residue can be present in unsubstituted ormono- or polysubstituted form, wherein the aryl substituents are thesame or different and can be in any desired and possible position of thearyl. Preferred aryls are phenyl, naphthyl, anthracenyl, phenanthrenyl,fluoroanthenyl, fluoroenyl, indanyl and tetralinyl. Phenyl and naphthylare particularly preferred. Where aryl is mono- or polysubstituted, thearyl substituents can be the same or different and be in any desired andpossible position of the aryl, and are selected independently of oneanother from the group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O,—R₀, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂,—OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀,—NHC(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂.Preferred substituted aryls are 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3-dimethyl-phenyl,2,4-dimethyl-phenyl and 3,4-dimethyl-phenyl.

Heteroaryl preferably stands for a 5-, 6- or 7-membered cyclic aromaticresidue that contains 1, 2, 3, 4 or 5 heteroatoms, wherein theheteroatoms, the same or different, are nitrogen, oxygen or sulphur, andthe heterocycle can be unsubstituted or mono- or polysubstituted;wherein in the case of the substitution on the heterocycle, thesubstituents can be the same or different and can be in any desired andpossible position of the heteroaryl; and wherein the heterocycle canalso be part of a bi- or polycyclic system. “Heteroaryl” is preferablyselected from the group comprising pyrrolyl, indolyl, furyl (furanyl),benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl,benzooxadiazolyl, benzothiazolyl, benzooxazolyl, benzotriazolyl,benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl,isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl oroxadiazolyl, wherein the bonding can occur via any desirable andpossible ring member of the heteroaryl residue. Where heteroaryl ismono- or polysubstituted, the heteroaryl substituents can be the same ordifferent and can be in any desirable and possible position of theheteroaryl, and are selected independently of one another from the groupcomprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀,—C(═O)OH, —C(═O)OR₀, —C(═O)—NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH,—O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NH—C(═O)R₀, —NHC(═O)OR₀,—NHC(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂.

With respect to “aryl” or “heteroaryl”, “mono- or polysubstituted” areunderstood to mean the mono- or polysubstitution, e.g. di-, tri-, 4- or5-substitution, of one or more hydrogen atoms of the ring system.

Particularly preferred are the substituents or aryl and heteroarylrespectively selected independently of one another from —F, —Cl, —Br,—I, —CN, —CHO, —CO₂H, —NH₂, —NO₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻,—SH, —SR₀, —OH, —OR₀, —C(═O)R₀, —CO₂R₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)N(R₀)₂, —S(═O)₁NH₂, —S(═O)₂NH₂, —SO₃H, ═O or —R₀. Preferredsubstituents are —F, —Cl, —Br, —I, —OH, —OC₁₋₆-alkyl,—O—C(═O)—C₁₋₆-alkyl, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C(═O)OC₁₋₆-alkyl or —C(═O)OH. Compounds, in which “aryl substituted” or“heteroaryl substituted” means aryl or heteroaryl substituted with —F,—Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃,—OC₂H₅ or —N(CH₃)₂, are preferred. Particularly preferred substituentsare —F, —Cl, —OH, —SH, —NH₂ and —C(═O)OH.

The compounds according to the invention can be present in the form of asingle stereoisomer or mixture thereof, the free compounds and/or theirphysiologically compatible salts and/or solvates.

The compounds according to the invention can be chiral or achiral,depending on the substitution pattern.

Depending on the substitution with respect to the cyclohexane ring thecompounds according to the invention can be isomers, in which thesubstitution pattern in 1,4 position (1 position: >C(NR₁R)R₃; 4position: >CQ((CH₂)_(n)XR_(B)) can also be referred to as syn/anti.“Syn/anti isomers” are a subgroup of the stereoisomers (configurationisomers).

In a preferred embodiment, the diastereomer excess of the syn-isomeramounts to at least 50% de, more preferred at least 75% de, morepreferred at least 90% de, most preferred at least 95% de, and inparticular at least 99% de. In another preferred embodiment, thediastereomer excess of the anti-isomer amounts to at least 50% de, morepreferred at least 75% de, more preferred at least 90% de, mostpreferred at least 95% de, and in particular at least 99% de.

Suitable methods for separating the isomers (diastereomers) are known tothe person skilled in the art. Column chromatography, preparative HPLCand crystallisation processes can be given as examples.

If the compounds according to the invention are chiral, then they arepreferably present as racemate or in concentrated form of an enantiomer.In a preferred embodiment the enantiomer excess(ee) of the S-enantiomeramounts at least 50% ee, more preferred at least 75% ee, more preferredat least 90% ee, most preferred at least 95% ee, and in particular atleast 99% ee. In another preferred embodiment, the enantiomer excess(ee) of the R-enantiomer amounts to at least 50% ee, more preferred atleast 75% ee, more preferred at least 90% ee, most preferred at least95% ee, and in particular at least 99% ee.

Suitable methods for separating the enantiomers are known to the personskilled in the art. Preparative HPLC on chiral stationary phases andconversion into diastereomeric intermediates can be given as examples.The conversion into diastereomeric intermediates can occur, for example,as salt formation by means of chiral, enantiomer-pure acids. Afterseparation of the diastereomers thus formed, the salt can then beconverted into the free base or another salt again.

Unless expressly specified, each reference to the compounds according tothe invention covers all isomers (e.g. stereoisomers, diastereomers,enantiomers) in any desired mixture ratio.

Unless expressly specified, each reference to the compounds according tothe invention covers the free compounds (i.e. the forms that are notpresent in the form of salt) and all physiologically compatible salts.

For the purposes of the description, physiologically compatible salts ofthe compounds according to the invention are present as salts withanions or acids of the respective compound with inorganic or organicacids, which are physiologically compatible—in particular on applicationin humans and/or mammals.

Examples of physiologically compatible salts of specific acids are saltsof: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid,malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid,citric acid, glutamic acid, saccharinic acid, monomethyl sebacic acid,5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or4-aminobenzoic acid, 2,4,6-trimethyl benzoic acid, α-liponic acid,acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.The hydrochloride, citrate and hemicitrate are particularly preferred.

Physiologically compatible salts with cations or bases are salts of therespective compound—as anion with at least one, preferably inorganic,cation, which are physiologically compatible—in particular onapplication in humans and/or mammals. Particularly preferred are thesalts of the alkali and earth alkali metals, also ammonium salts, but inparticular (mono-) or (di-) sodium, (mono-) or (di-) potassium,magnesium or calcium salts.

Respectively preferred embodiments of the compounds according to theinvention are explained below. Unless expressly specified, alldefinitions of the respective substituents explained previously (i.e.from R₀ to R₄, Y₁ to Y₄′, Q etc., for example) and their respectiveembodiments apply accordingly and will not therefore be repeated.

Preferred embodiments of the compounds according to the invention of thegeneral formula (1) have the general formula (2):

wherein

(hetero)aryl stands for hetereoaryl or aryl; preferably phenyl;respectively unsubstituted or mono- or polysubstituted, wherein thesubstituents are preferably selected independently of one another fromthe group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀,—C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NH—R₀, —C(═O)—N(R₀)₂,—OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)—OR₀,—NH—C(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; more preferred —F, —Cl,—Br, —I, —CF₃, —CN and —NO₂.

Particularly preferred embodiments of the compounds according to theinvention of the general formula (2) have the general formula (2.1),(2.2), (2.3), (2.4), (2.5), (2.6), (2.7), (2.8), (2.9), (2.10), (2.11),(2.12), (2.13) or (2.14):

wherein

R_(C) stands for —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —OH or —OCH₃;and, where present,

(hetero)aryl stands for heteroaryl or aryl; preferably for -phenyl,-benzyl or -2-indolyl; respectively unsubstituted or mono- orpolysubstituted, wherein the substituents are preferably selectedindependently of one another from the group comprising —F, —Cl, —Br, —I,—CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂,—C(═O)—NH—R₀, —C(═O)—N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H,—OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H,—S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻,—NHC(═O)R₀, —NHC(═O)—OR₀, —NH—C(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂;more preferred —F, —Cl, —Br, —I, —CF₃, —CN and —NO₂; and

m stands for 0, 1, 2, 3, 4, 5 or 6.

Preferred representatives of the compounds of the general formula (2.14)are e.g. the compounds E-1 to E-12:

Further preferred embodiments of the compounds according to theinvention of the general formula (1) have the general formula (3):

wherein

Q′ stands for —(CH₂)₀₋₄—, —C(═O)— or —C(═NH)—; and

(hetero-)aryl stands for heteroaryl or aryl; preferably phenyl;respectively unsubstituted or mono- or polysubstituted, wherein thesubstituents are preferably selected independently of one another fromthe group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀,—C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NH—R₀, —C(═O)—N(R₀)₂,—OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)—OR₀,—NH—C(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; more preferred —F, —Cl,—Br, —I, —CF₃, —CN and —NO₂.

Particularly preferred embodiments of the compounds according to theinvention of general formula (3) have the general formula (3.1), (3.2),(3.3), (3.4), (3.5), (3.6), (3.7) or (3.8):

wherein, where present,

D stands for ═O or ═NH;

W stands for —O—, —S—, —NR₁₁—, —CR₁₂═CR₁₃—, —CR₁₂═N— or —N═CR₁₃—;preferably for —O—, —S—, or —NR₁₁—; particularly preferred for —NR₁₁—;

R₅, R₆, R₆′, R₁₁, R₁₂ and R₁₃ respectively independently of one anotherstand for —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H,—C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)—N(R₀)₂, —OH,—O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀,—NH—C(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂; or R₅ and R₆, or R₆ and R₆′,or R₆′ and R₁₂ together form a five- or six-membered, saturated,partially unsaturated or aromatic, unsubstituted or mono- orpolysubstituted ring, which possibly comprises one or two hetero ringatoms selected independently of one another from N, S and O;

A₁ stands for —N═ or —CR₇═,

A₂ stands for —N═ or —CR₈═,

A₃ stands for —N═ or —CR₉═,

A₄ stands for —N═ or —CR₁₀═;

on condition that at most two of the residues A₁, A₂, A₃ and A₄,preferably 0, 1 or 2 of the residues A₁, A₂, A₃ and A₄, stand for —N═;

R₇, R₈, R₉ and R₁₀ respectively independently of one another stand for—H, —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₁₄, —SR₁₄, —SO₂R₁₄, —CN, —COOR₁₄,—CONR₁₄, —NR₁₅R₁₆, ═O or —R₀; preferably for —F, —Cl, —Br, —I, —CF₃, —CNor —NO₂;

R₁₄ respectively independently stands for —H or —R₀;

R₁₅ and R₁₆ independently of one another stand for —H or —R₀; or R₁₅ andR₁₆ together stand for —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₄CH₂CH₂— or —(CH₂)₃₋₆—.

If, for example, W stands for —CR₁₂═CR₁₃—, —CR₁₂═N— or —N═CR₁₃—, thenthe following functional groups preferably result:

If, for example, R₆ and R₆′ together form a six-membered aromatic ringthat has no hetero ring atoms, then the following functional groupsrespectively result:

The five- or six-membered, saturated, partially unsaturated or aromaticring possibly formed by R₅ and R₆ or R₆ and R₆′ or R₆′ and R₁₂ togethercan comprise one or two hetero ring atoms, which are selectedindependently of one another from N, S and O. Moreover, this ring can beunsubstituted or mono- or polysubstituted, wherein the substituents arepreferably selected independently of one another from the groupcomprising F, —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H,—C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)—N(R₀)₂, —OH,—O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀,—NH—C(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; more preferred —F, —Cl,—Br, —I, —CF₃, —CN and —NO₂.

R₅ preferably stands for —H, —F, —Cl or —R₀; more preferred for —H, —F,—C₁₋₈-aliphatic, —C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl or—C₁₋₈-aliphatic-O—C₁₋₈-aliphatic (e.g. —CH₂OCH₃). It is preferred if R₆and R₆′ together form a six-membered, saturated, partially unsaturatedor aromatic ring, which can possibly comprise one or two hetero ringatoms that are selected independently of one another from N, S and O.This formed ring can be unsubstituted or mono- or polysubstituted,wherein the substituents are preferably selected independently of oneanother from the group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO,—R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)—N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,—OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NH—C(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; morepreferred —F, —Cl, —Br, —I, —CF₃, —CN and —NO₂.

R₁₁, R₁₂ and R₁₃ are preferably selected independently of one anotherfrom the group comprising —H, —F, —Cl, —CN, —OH, —R₀ and —OR₀. It isparticularly preferred if R₁₁, R₁₂ and R₁₃—where present—arerespectively —H.

Further preferred embodiments of the compounds according to theinvention of the general formula (1) have the general formula (4):

wherein

(hetero)aryl stands for heteroaryl or aryl; preferably phenyl;respectively unsubstituted or mono- or polysubstituted, wherein thesubstituents are preferably selected independently of one another fromthe group comprising —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀,—C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NH—R₀, —C(═O)—N(R₀)₂,—OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,—OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂,—NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)—OR₀,—NH—C(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; more preferred —F, —Cl,—Br, —I, —CF₃, —CN and —NO₂.

The compounds according to the invention are defined by substituents,e.g. by R₁, R₂ and R₃ (substituents of the first generation), which arethemselves possibly substituted (substituents of the second generation).Depending on the definition, these substituents of the substituents canthemselves be substituted again (substituents of the third generation).If, for example, Y₁=—R₀, wherein —R₀=—C₁₋₈-aliphatic (substituent of thefirst generation), then —C₁₋₈-aliphatic can itself be substituted, e.g.with —OR₀, wherein R₀=-aryl (substituent of the second generation). Thisgives the functional group —C₁₋₈-aliphatic-Oaryl. -Aryl can then in turnbe substituted again, e.g. with —Cl (substituent of the thirdgeneration). This then gives overall the functional group—C₁₋₈-aliphatic-Oaryl-Cl.

In a preferred embodiment, the substituents of the third generationcannot be substituted again, i.e. there are then no substituents of thefourth generation.

In another preferred embodiment, the substituents of the secondgeneration cannot be substituted again, i.e. there are then already nosubstituents of the third generation. In other words, in this embodimentthe functional groups for R₀ to Y₄′ can possibly be respectivelysubstituted, but the respective substituents cannot then themselves besubstituted again.

In another preferred embodiment, the substituents of the firstgeneration cannot be substituted again, i.e. there are then neithersubstituents of the second generation nor substituents of the thirdgeneration. In other words, in this embodiment the functional groups forR₀ to Y₄′ are not respectively substituted.

Embodiments of the compounds of the general formula (1) that areparticularly preferred according to the invention are compounds of thegeneral formula (2.2)

wherein

Q stands for —C₁₋₈-aliphatic (preferably —C₁₋₈-alkyl), -aryl (preferably-phenyl), —C₁₋₈-aliphatic-aryl (preferably —C₁₋₈-alkyl-phenyl),-heteroaryl (preferably -indolyl), —C(═O)-heteroaryl (preferably—C(═O)-indolyl) or —C(═NH)-heteroaryl (preferably —C(═NH)-indolyl);

R₁ stands for —CH₃;

R₂ stands for —H or —CH₃; or

R₁ and R₂ jointly form a ring and stand for —(CH₂)₃₋₄—;

X stands for —O— or —NR_(A)—;

R_(A) stands for —H or —C₁₋₈-aliphatic (preferably —C₁₋₈-alkyl);

R_(B) stands for —H, —C₁₋₈-aliphatic (preferably —C₁₋₈-alkyl),—C₁₋₈-aliphatic-aryl (preferably —C₁₋₈-alkyl-phenyl),—C₁₋₈-aliphatic-heteroaryl (preferably —C₁₋₈-alkyl-indolyl), aliphatic(preferably —C(═O)—C₁₋₈-alkyl), —C(═O)—C₁₋₈-aliphatic-aryl (preferably—C(═O)-benzyl), —C(═O)—C₁₋₈-aliphatic-heteroaryl (preferably—C(═O)—C₁₋₈-alkyl-indolyl), —C(═O)—C₃₋₈-cycloaliphatic-aryl (preferably—C(═O)-cyclopropyl-aryl), —C(═O)—C₃₋₈-cycloaliphatic-heteroaryl(preferably —C(═O)-cyclopropyl-heteroaryl), —C(═O)NH—C₁₋₈-aliphatic(preferably —C(═O)NH—C₁₋₈-alkyl), —S(═O)₁₋₂—C₁₋₈-aliphatic (preferably—S(═O)₂—C₁₋₈-alkyl), —S(═O)₁₋₂-aryl (preferably —S(═O)₂-phenyl),—S(═O)₁₋₂-heteroaryl, —S(═O)₁₋₂—C₁₋₈-aliphatic-aryl,—S(═O)₁₋₂—C₁₋₈-aliphatic-heteroaryl, —S(═O)₁₋₂—C₃₋₈-cycloaliphatic-aryl(preferably —S(═O)₂-cyclopropyl-aryl) or—S(═O)₁₋₂—C₃₋₈-cycloaliphatic-heteroaryl (preferably—S(═O)₂-cyclopropyl-heteroaryl); or R_(A) and R_(B) jointly form a ringand stand for —(CH₂)₃₋₄—; on condition that when X stands for —O— and nat the same time stands for 0, R_(B) does not stand for —H;

R_(C) stands for —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —OH or —OCH₃;and

n stands for 0, 1, 2, 3 or 4;

wherein aliphatic, aryl and heteroaryl are respectively unsubstituted ormono- or polysubstituted.

Compounds from the following group are most particularly preferred:

-   1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine    bis(2-hydroxypropane-1,2,3-tricarboxylate);-   4-(dimethylamino)-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)(1-methyl-1H-indol-2-yl)methanone;-   1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine    bis(2-hydroxypropane-1,2,3-tricarboxylate);-   1,4-bis(dimethylamino)-4-phenylcyclohexyl)(1-methyl-1H-indol-2-yl)methanone;-   4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine;-   4-(dimethylamino)-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)(1-methyl-1H-indol-2-yl)methanone;-   N1,N1,N4-trimethyl-1,4-diphenylcyclohexane-1,4-diamine;-   N1,N1,N4,N4-tetramethyl-1,4-diphenylcyclohexane-1,4-diamine;-   1-benzyl-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine;-   4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexan-amine    2-hydroxypropane-1,2,3-tricarboxylate;-   4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenyl-cyclohexanamine;-   4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine    2-hydroxypropane-1,2,3-tricarboxy late;-   N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)acetamide    2-hydroxypropane-1,2,3-tricarboxylate;-   4-chloro-N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzol-sulphonamide    2-hydroxypropane-1,2,3-tricarboxylate;-   N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzol-sulphonamide    2-hydroxypropane-1,2,3-tricarboxylate;-   N-((−4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol;-   N(4-((dimethylamino)methyl)-N,N-dimethyl-1,4-diphenylcyclohexanamine;-   4-benzyl-4-((dimethylamino)methyl)-N,N-dimethyl-1-phenylcyclohexanamine;-   4-(((1H-indol-2-yl)methylamino)methyl)-N,N,4-trimethyl-1-phenylcyclohexanamine;-   N1,N1,N4,N4-tetramethyl-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexane-1,4-diamine;-   N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-methyl-cinnamamide;-   N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-methyl-acetamide;-   [4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamine;-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethylamine    (non-polar diastereomer);-   (E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-acetamide    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulphonamide    (polar diastereomer);-   (E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide    (polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-acetamide    (polar diastereomer);-   3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea    (non-polar diastereomer);-   3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea    (polar diastereomer);-   1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea    (non-polar diastereomer);-   1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea    (polar diastereomer);-   (4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine    (polar diastereomer);-   (1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethylamine    (polar diastereomer);-   [4-(dimethylamino)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-dimethylamino-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   dimethyl-(4-methylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine    (non-polar diastereomer);-   dimethyl-(4-methylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine    (polar diastereomer);-   [4-(dimethylamino)-4-phenyl-1-thiophen-2-yl-cyclohexyl]-dimethylamine    (polar diastereomer);-   (4-dimethylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-dimethylamine    (non-polar diastereomer);-   (E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide    (polar diastereomer);-   (E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide    (non-polar diastereomer);-   (E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-2-phenyl-ethylene    sulphonamide (non-polar diastereomer);-   (E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-2-phenyl-ethylene    sulphonamide (polar diastereomer);-   (1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethylamine (non-polar    diastereomer);-   (1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethylamine (polar    diastereomer);-   [4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   N-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-acetamide    (polar diastereomer);-   dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-amine    dihydrochloride (polar diastereomer);-   dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-amine;-   [4-(acetidin-1-yl)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulphonamide    (non-polar diastereomer);-   (4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethylamine    (non-polar diastereomer);-   (4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethylamine (polar    diastereomer);-   [4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methylamine    (non-polar diastereomer);-   [4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methylamine    (polar diastereomer);-   [4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   (E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide    (non-polar diastereomer);-   (E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide    (polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic    acid (polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic    acid (non-polar diastereomer);-   [1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine    (non-polar diastereomer);-   dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine    (polar diastereomer);-   [4-(dimethylamino)-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-dimethylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(dimethylamino)-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [3-[[[4-(dimethyl-amino)-1-methyl-4-phenyl-cyclohexyl]-methyl-methylamino]-methyl]-1H-indol-1-yl]-methanol    (polar diastereomer);-   (E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide    (polar diastereomer);-   [4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methylamine    (polar diastereomer);-   [4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methylamine    (non-polar diastereomer);-   benzyl-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-amine;    2-hydroxy-propane-1,2,3-tricarboxylic acid;-   dimethyl-[4-[methyl-(pyridin-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine    (polar diastereomer);-   [4-[[4,6-bis(methylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N-methyl-pyridin-3-carboxylic    acid amide (non-polar diastereomer);-   dimethyl-[4-[methyl-(pyridin-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine    (non-polar diastereomer);-   [4-[[4,6-bis(methylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazol-3-carboxylic    acid amide (polar diastereomer);-   N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazol-3-carboxylic    acid amide (non-polar diastereomer);-   [4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine    (polar diastereomer);-   4-(acetidin-1-yl)-1-(3-fluorophenyl)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine    (non-polar diastereomer);-   4-(acetidin-1-yl)-1-(3-fluorophenyl)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine    (polar diastereomer);-   [4-dimethylamino-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide    (polar diastereomer);-   [4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazol-3-yl)-methyl]-amine    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazol-3-yl)-methyl]-amine    (non-polar diastereomer);-   [4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methylamine    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methylamine    (non-polar diastereomer);-   [1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [1-(3-fluorophenyl)-4-methylamino-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine;-   dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-piperidin-1-yl-cyclohexyl]-amine    (non-polar diastereomer);-   [1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-piperidin-1-yl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-(dimethylamino)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide    (non-polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-fluorophenyl)-methyl]-methylamine    (non-polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-fluorophenyl)-methyl]-methylamine    (polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol    (polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl-acetamide    (polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-acetamide    (polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl-acetamide    (non-polar diastereomer);-   2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-acetamide    (non-polar diastereomer);-   [4-dimethylamino-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   2-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol    (non-polar diastereomer);-   [4-[[4,6-bis(dimethylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   dimethyl-[4-[methyl-(4-methylamino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine    (polar diastereomer);-   4-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butan-1-ol    (polar diastereomer);-   3-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-carbamoyl]-propionic    acid (polar diastereomer);-   [4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-piperidin-1-yl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(acetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-fluorophenyl)-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(acetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-fluorophenyl)-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholin-4-yl-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   dimethyl-[4-methylamino-4-(3-methyl-1H-indol-2-yl)-1-thiophen-2-yl-cyclohexyl]-amine    (polar diastereomer);-   [4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholin-4-yl-1-phenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[(4-anilino-6-methylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[[4-(isopropyl-methyl-amino)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[(4-anilino-6-methylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[[4-(benzylamino)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[(4-butylamino-6-methylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   (1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-methylamine (polar    diastereomer);-   (1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-methylamine (non-polar    diastereomer);-   [4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine;-   [4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-thiophen-2-yl-cyclohexyl]-methylamine    (non-polar diastereomer);-   (1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-dimethylamine (polar    diastereomer);-   (1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-dimethylamine (non-polar    diastereomer);-   [4-[[4-(benzylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   dimethyl-[4-[methyl-(4-piperidin-1-yl-[1,3,5]triazin-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine    (polar diastereomer);-   [4-[(4-butylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[(4-anilino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[[4-(isopropyl-methyl-amino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-[[4-(tert-butylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   [4-(cyclohexyl-methylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-(cyclopentylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-anilino-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine;-   [1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-(pyridin-4-ylamino)-cyclohexyl]-dimethylamine;-   [4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine    (non-polar diastereomer);-   [4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine    (polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-cyclohexane    carboxylic acid amide (polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-tetrahydro-pyran-4-carboxylic    acid amide (polar diastereomer);-   cyclohexyl-methyl-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methylamine    (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-(tetrahydro-pyran-4-yl-methyl)-amine    (polar diastereomer);-   N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N,1-dimethyl-piperidin-4-carboxylic    acid amide (polar diastereomer);-   (4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-piperidin-4-yl)-methyl]-amine    (polar diastereomer);    and physiologically compatible salts and/or solvates thereof.

The compounds according to the invention act, for example, on therelevant ORL 1-receptor in association with different diseases, andtherefore they are suitable as pharmaceutical active substance in amedication.

Therefore, the invention additionally relates to medications, whichcontain at least one compound according to the invention, as well aspossibly suitable additives and/or adjuvants and/or possibly furtheractive substances.

The compounds according to the invention have an affinity to theμ-opioid or to the ORL 1-receptor comparable to the compounds disclosedas exemplary compounds in WO 03/008370. However, compared to thesecompounds they exhibit a higher selectivity with respect to μ-opioidreceptor, which is responsible for side-effects such as e.g. dysphoria,sedation and diuresis. In addition, with a favourable ORL 1/μ affinitythe compounds according to the invention exhibit a balanced affinity tothe μ-opioid receptor that is not too strong. This is an advantage,since the μ-opioid receptor is associated with side-effects, inparticular respiratory depression, constipation and addictiondependence. Therefore, they are particularly suitable for drugdevelopment.

Besides at least one compound according to the invention, themedications according to the invention possibly contain suitableadditives and/or adjuvants, hence also support materials, fillers,solvents, dilutants, colouring agents and/or binders, and can beadministered as liquid medications in the form of injectable solutions,drops or juices, as semisolid medications in the form of granules,tablets, pellets, patches, capsules, plasters/spray plasters oraerosols. The selection of adjuvants etc. as well as the quantitiesthereof to be used are dependent on whether the medication is to beapplied orally, perorally, parenterally, intravenously,intraperitoneally, intradermally, intramuscularly, intranasally,bucally, rectally or locally, e.g. onto the skin, mucous membranes orinto the eyes. Preparations in the form of tablets, coated tablets,capsules, granules, drops, juices and syrups are suitable for oralapplication, solutions, suspensions, readily reconstituted drypreparations as well as sprays are suitable for parenteral, topical andinhalatory application. Compounds according to the invention in a depot,in dissolved form or in a plaster, possibly with the addition ofskin-penetration promoters, are suitable preparations for percutaneousapplication. Preparation forms that may be applied orally orpercutaneously can release the compounds according to the invention in adelayed manner. The compounds according to the invention can also beapplied in parenteral long-term depot forms such as e.g. implants orimplanted pumps. In principle, other additional active substances knownto the skilled person can be added to the medications according to theinvention.

The amount of active substance to be administered to the patient variesdepending on the weight of the patient, on the type of application, theindication and the degree of severity of the disease. Usually, 0.00005to 50 mg/kg, preferably 0.001 to 0.5 mg/kg, of at least one compoundaccording to the invention are applied.

For all the above-mentioned forms of the medication according to theinvention it is particularly preferred if, besides at least one compoundaccording to the invention, the medication also contains a furtheractive substance, in particular an opioid, preferably a strong opioid,in particular morphine, or an anaesthetic, preferably hexobarbital orhalothane.

In a preferred form of the medication, a contained compound according tothe invention is present in the form of pure diastereomer and/orenantiomer.

The ORL 1-receptor was identified in particular in the pain process.Compounds according to the invention can be used accordingly for theproduction of a medication for the treatment of pain, in particular ofacute, neuropathic or chronic pain.

Therefore, the invention additionally relates to the use of a compoundaccording to the invention for the production of a medication for thetreatment of pain, in particular of acute, visceral, neuropathic orchronic pain.

The invention further relates to the use of a compound according to theinvention for the treatment of anxiety conditions, stress andstress-related syndromes, depressive illnesses, epilepsy, Alzheimer'sdisease, senile dementia, general cognitive dysfunctions, learning andmemory disabilities (as nootropic), withdrawal symptoms, alcohol and/ordrug and/or medication misuse and/or dependence, sexual dysfunctions,cardiovascular diseases, hypotension, hypertension, tinitus, pruritus,migraine, hearing impairment, deficient intestinal motility, eatingdisorders, anorexia, bulimia, mobility disorders, diarrhoea, cachexia,urinary incontinence, or as muscle relaxant, anticonvulsive oranaesthetic, or for coadministration in the treatment with an opioidanalgesic or with an anaesthetic, for diuresis or anti-natriuresis,anxiolysis, for modulating movement activity, for modulatingneurotransmitter release and for treating neuro-degenerative diseasesassociated therewith, for treating withdrawal symptoms and/or forreducing the addiction potential of opioids.

In this case, it can be preferred in one of the above uses if a usedcompound is present as a pure diastereomer and/or enantiomer, as aracemate or as non-equimolar or equimolar mixture of the diastereomersand/or enantiomers.

The invention additionally relates to a method for treating, inparticular in one of the aforementioned indications, a non-human mammalor human, which or who requires a treatment for pain, in particularchronic pain, by the administration of a therapeutically effective doseof a compound according to the invention or a medication according tothe invention.

The invention further relates to a method for producing the compoundsaccording to the invention as outlined in the following description andexamples.

a) Synthesis of cyclohexane-1,4-diamines

Method 1:

Structures of formula A-2 can be produced by the reaction of A-1 ketoneswith amines and Z—H acid reactants. Suitable Z—H reactants are e.g.hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.

A particularly preferred path to compounds of structure A-2 is theconversion of ketones with metal cyanides and the corresponding amine inthe presence of acid, preferably in an alcohol, at temperatures of −40to 60° C., preferably at room temperature with alkali metal cyanides inmethanol.

A further particularly preferred path to compounds of structure A-2 isthe conversion of ketones with 1,2,3-triazole and the correspondingamine in the presence of ? under dehydrating conditions, preferablyusing a water separator at elevated temperature in an inert solvent orusing a molecular sieve or another dehydrating agent. Similarly,structures similar to A-2 can be introduced with benzotriazole orpyrazole groups instead of triazole groups. In general, A-3cyclohexane-1,4-diamines can also be obtained by substituting suitable Zleaving groups in structures of formula A-2. Suitable leaving groups arepreferably cyano groups; 1,2,3-triazol-1-yl groups. Further suitableleaving groups are 1H-benzo[d][1,2,3]triazol-1-yl groups andpyrazol-1-yl groups (Katritzky et al., Synthesis 1989, 66-69).

A particularly preferred path to compounds of structure A-3 is theconversion of A-2 aminonitriles with corresponding organometalliccompounds, preferably Grignard compounds, preferably in ethers,preferably at RT. The organometallic compounds are either commerciallyavailable or can be produced using known methods. A further particularlypreferred path to compounds of structure A-3 is the conversion of A-2aminotriazoles with corresponding organometallic compounds, preferablyGrignard compounds, preferably in ethers, preferably at RT.

The organometallic compounds are either commercially available or can beproduced using methods known in specialist literature.

Method 2:

Structures of formula A-4 can be produced by reacting A-1 ketones withprimary amines and Z—H acid reactants. Suitable Z—H reactants are e.g.hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.

A particularly preferred path to compounds of structure A-4 is theconversion of ketones with metal cyanides and the corresponding amine inthe presence of acid, preferably in an alcohol, at temperatures of −40to 60° C., preferably at room temperature with alkali metal cyanides inmethanol.

A further particularly preferred path to compounds of structure A-4 isthe conversion of ketones with 1,2,3-triazole and the correspondingamine in the presence of ? under dehydrating conditions, preferablyusing a water separator at elevated temperature in an inert solvent orusing a molecular sieve or another dehydrating agent. Similarly,structures similar to A-4 can be introduced with benzotriazole orpyrazole groups instead of triazole groups.

In general, A-5 cyclohexane-1,4-diamines can also be obtained bysubstituting suitable Z leaving groups in structures of formula A-4.Suitable leaving groups are preferably cyano groups; 1,2,3-triazol-1-ylgroups. Further suitable leaving groups are1H-benzo[d][1,2,3]triazol-1-yl groups and pyrazol-1-yl groups (Katritzkyet al., Synthesis 1989, 66-69).

A particularly preferred path to compounds of structure A-5 is theconversion of A-4 aminonitriles with corresponding organometalliccompounds, preferably Grignard compounds, preferably in ethers,preferably at RT. The organometallic compounds are either commerciallyavailable or can be produced using known methods. A further particularlypreferred path to compounds of structure A-5 is the conversion of A-4aminotriazoles with corresponding organometallic compounds, preferablyGrignard compounds, preferably in ethers, preferably at RT.

The organometallic compounds are either commercially available or can beproduced using methods known in specialist literature.

Cyclohexane-1,4-diamines of type A-3 can also be synthesised usingmethods known to the person skilled in the art. An introduction of(alkyl) substituents can then occur under conditions of a reductiveamination by means of an aldehyde component. Such a method known to theskilled person can be the conversion with an aldehyde with the additionof a reducing agent, e.g. sodium boron hydride.

b) Synthesis of (1,4-diaminocyclohexyl)(heteroaryl)methanones

Substituted (1,4-diaminocyclohexyl)(heteroaryl)methanones of type A-7,X═O can be synthesised from the above-described A-2 educt, Z═CN, usingmethods known to the person skilled in the art. By converting metallisedheterocycles of type A-6 with the triple bond of A-2, Z═CN, theintermediate A-7, X═NH is obtained. A hydrolysis under acid conditionsthen results by splitting imine A-7, X═O.

c) Synthesis of 4-alkoxycyclohexane-1-amines

Substituted 4-alkoxycyclohexane-1-amines of type A-10 can be synthesisedfrom the A-1 educt using methods known to the person skilled in the art.The alcoholate obtained by the reaction of metallised alkines with A-1is converted to A-8 with the corresponding electrophiles e.g. of typeR₀X (with X=e.g. Br, I, OTos, OTf etc.). The conversion of A-9 carbinolsto the substituted 4-alkoxycyclohexane-1-amines of type A-10 accordingto the invention can occur in organic solvents, e.g. tetrahydrofuran,dimethylformamide, benzol, toluol, xylols, dimethoxyethane or diethyleneglycol dimethyl ether, in the presence of an inorganic base, e.g.sodium, potassium or caesium carbonate or potassium phosphate in thepresence of PdCl₂, Pd(OAc)₂, PdCl₂(MeCN)₂, PdCl₂(PPh₃)₂ or[1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride)(PEPPSI®),possibly in the presence of additional ligands, e.g. triphenyl-,tri-o-tolyl-, tricyclohexyl or tri-t-butyl phosphine, possibly in thepresence of phase transfer catalysts, e.g. tetra-n-butyl ammoniumchloride, tetra-n-butyl ammonium hydroxide or tetra-n-butyl ammoniumiodide, and at temperatures between 60° C. and 180° C., alsomicrowave-assisted.

d) Synthesis of 4-aminomethyl-cyclohexyl-1-amines

Substituted 4-aminomethyl-cyclohexyl-1-amines of type A-14 can besynthesised from the known A-1 educts by methods known to the personskilled in the art. Working from ketones such as A-1, the intermediateA-11 alkenes are obtained by a Wittig olefination with phosphorusylides. Compounds of formula A-12 can then be obtained from thecorresponding A-11 precursors in the presence of a cobalt(II)-salencomplex by hydrocyanation (Carreira et al. Angew. Chem. Int. Ed., 46,2006, 4519). A conversion of the nitrile group in A-12 with a reducingagent, e.g. a hydride such as sodium or lithium boron hydride, sodiumcyanoboron hydride, sodium triacetoxyboron hydride, diisobutyl aluminiumhydride, lithium-tri-(sec-butyl)boron hydride (L-Selectride®) or lithiumaluminium hydride, possibly in the presence of Lewis acids, e.g. ZnCl₂,Ni(OAc)₂ or CoCl₂, gives the A-13 amines.

Method 1:

Amines of type A-13 can be acylated, sulphonylated or carbamoylated tocompounds of A-14 using methods known to the person skilled in the art.Such a method known to the skilled person can be the conversion with ananhydride or an acid chloride with the addition of a base, e.g.triethylamine.

Method 2:

Amines of type A-13 can be reductively aminated to compounds of A-14using methods known to the person skilled in the art. Such a methodknown to the skilled person can be the conversion with an aldehyde withthe addition of a reducing agent, e.g. sodium boron hydride.

d) Synthesis of (4-aminocyclohexyl)methanols

Substituted (4-aminocyclohexyl)methanols of type A-18 can be synthesisedfrom the known A-15 educts by methods known to the person skilled in theart. The deprotonation of A-15 esters with a base, e.g. lithiumdiisopropylamide (LDA), and conversion with the correspondingelectrophiles, e.g. of type R₀—X (with X=e.g. Br, I, OTos, OTf etc.), toA-16 is described in the specialist literature (Williams et al. J. Org.Chem. 1980, 45, 5082; Shiner et al. J. Am. Chem. Soc. 1981, 103, 436;Xia et al. Org. Lett. 2005, 7, 1315). A conversion of A-16 can occurwith a reducing agent, e.g. a hydride such as sodium or lithium boronhydride, sodium cyanoboron hydride, sodium triacetoxyboron hydride,diisobutyl aluminium hydride, lithium-tri-(sec-butyl)boron hydride(L-Selectride®) or lithium aluminium hydride, possibly in the presenceof Lewis acids, e.g. ZnCl₂, Ni(OAc)₂ or CoCl₂, and ketone acetalsplitting using methods known to the skilled person by deprotection bymeans of acids. In this case, X is selected from the group alkyl,alkyl/alkylidene/alkylidene substituted with aryl or alkyl(saturated/unsaturated). A protection of the hydroxyl group according tomethods known to the skilled person, e.g. by conversion with alkyl vinylethers, leads to the corresponding A-17 α-alkyloxy ethyl ethers.

Structures of formula A-18 can be produced by reaction of A-17 ketoneswith amines and Z—H acid reactants. Suitable Z—H reactants are e.g.hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.

A particularly preferred path to such aminonitriles is the conversion ofketones with metal cyanides and the corresponding amine in the presenceof acid, preferably in an alcohol, at temperatures of −40 to 60° C.,preferably at room temperature with alkali metal cyanides in methanol.

A further particularly preferred path to such aminonitriles is theconversion of ketones with 1,2,3-triazole and the corresponding amine inthe presence of ? under dehydrating conditions, preferably using a waterseparator at elevated temperature in an inert solvent or using amolecular sieve or another dehydrating agent. Similarly, similarstructures can be introduced with benzotriazole or pyrazole groupsinstead of triazole groups.

The introduction of the residue R₃ can occur by substitution of suitableZ leaving groups such as has already been described for the conversionof A-2 to A-3, for example.

Compounds of formula A-18 can be released from corresponding acetals orfrom their salts by deprotection by means of acids using methods knownto the skilled person. In this case, PG is selected from the group ofacetal protective groups for hydroxyl groups known to the skilledperson, e.g. an α-alkyloxy ethyl ether protective group.

e) Synthesis of 4-indolyl cyclohexane-1,4-diamines Method 1:

Step 1:

The keto group can be converted into monomethyl aminonitrile usingmethods known from the specialist literature, in particular applying theliterature texts relevant to the synthesis of A-1.

Step 2:

A-19 aminonitriles can be converted into A-20 alkine derivatives withcorresponding organometallic compounds, preferably organo-lithium andGrignard compounds, preferably in ethers, preferably at RT. Theorganometallic compounds are either commercially available or can beproduced using known methods.

Step 3:

A-20 alkine derivatives can be converted into the protected A-21 indolederivatives according to F. Messina et al./Tetrahedron: Asymmetry 11(2000) 1681-1685.

Step 4:

A-21 indole derivatives can be converted to A-22 indole derivativesusing methods known from specialist literature (cf. Protective Groups inOrganic Synthesis by Peter G. M. Wuts, Theodora W. Greene,WileyBlackwell; 4th Edition).

Step 5:

A-22 indole derivatives can be converted into A-23 amides using methodsknown to the skilled person. Such a method known to the skilled personcan be, for example, the conversion of A-22 with a carboxylic acid byadding a coupling reagent, e.g. carbonyl di-imidazole.

A-22 indole derivatives can be converted into A-23 sulphonamides usingmethods known to the skilled person. Such a method known to the skilledperson can be, for example, the conversion of A-22 with a sulphonylchloride by adding a base, e.g. triethylamine.

A-22 indole derivatives can be converted into A-23 amines using methodsknown to the skilled person. Such a method known to the skilled personcan be, for example, the conversion of A-22 with an aldehyde by adding areducing reagent, e.g. sodium boron hydride.

Method 2:

Substituted cyclohexanamines of type A-25 can be synthesised from theA-1 educt by reaction with metallised alkines. The conversion of theA-8′ and A-9 carbinols to substituted 4-alkoxycyclohexane-1-amines oftype A-10′ can occur in organic solvents, e.g. tetrahydrofuran,dimethylformamide, benzol, toluol, xylols, dimethoxyethane or diethyleneglycol dimethyl ether, in the presence of an inorganic base, e.g.sodium, potassium or caesium carbonate or potassium phosphate in thepresence of PdCl₂, Pd(OAc)₂, PdCl₂(MeCN)₂, PdCl₂(PPh₃)₂ or[1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride(PEPPSI®), possibly in the presence of additional ligands, e.g.triphenyl-, tri-o-tolyl-, tricyclohexyl or tri-t-butyl phosphine,possibly in the presence of phase transfer catalysts, e.g. tetra-n-butylammonium chloride, tetra-n-butyl ammonium hydroxide or tetra-n-butylammonium iodide, and at temperatures between 60° C. and 180° C., alsomicrowave-assisted. Alternatively, a conversion of A-9′ metallisedheterocycles with A-1 educt in organic solvents at temperatures between24° C. and −100° C. can also lead to carbinols of type A-10′. Thesubsequent cyclisation of A-10′ to the A-24 ammonium salt can occur inorganic solvents in the presence of fluorinating agents at temperaturesbetween 25° C. and −100° C. The opening up of the A-24 salt to thesubstituted cyclohexanamines of type A-25 according to the invention canoccur with suitable nucleophiles without or also in the presence oforganic solvents at temperatures between 0° C. and 180° C., alsomicrowave-assisted.

f) Synthesis of N-heteroaryl-1,4-diamines

Substituted cyclohexanamines of type A-26 and A-27 can be synthesisedfrom the A-5 educt. The A-3′ intermediate is obtained by the reaction ofheterocycles (method 1) or cyanates (method 2) with suitable leavinggroups (e.g. with LG=Cl or 4-OMe-C₆H₄). The remaining leaving groups canbe successively replaced by suitable nucleophiles (Nu) and thesubstituted cyclohexanamines of type A-26 and A-27 according to theinvention are obtained.

g) Preliminary Steps

Compounds of the general formulae A-1 and A-15 are either commerciallyavailable or their production is known from the prior art or can bederived from the prior art in an obvious manner for the skilled person.Particularly relevant in this case are the following citations:Jirkovsky et al., J. Heterocycl. Chem., 12, 1975, 937-940; Beck et al.,J. Chem. Soc. Perkin 1, 1992, 813-822; Shinada et al., TetrahedronLett., 39, 1996, 7099-7102; Garden et al., Tetrahedron, 58, 2002,8399-8412; Lednicer et al., J. Med. Chem., 23, 1980, 424-430; Bandini etal. J. Org. Chem. 67, 15; 2002, 5386-5389; Davis et al., J. Med. Chem.35, 1, 1992, 177-184; Yamagishi et al., J. Med. Chem. 35, 11, 1992,2085-2094; Gleave et al.; Bioorg. Med. Chem. Lett. 8, 10, 1998,1231-1236; Sandmeyer, Helv. Chim. Acta; 2; 1919; 239; Katz et al.; J.Med. Chem. 31, 6, 1988; 1244-1250; Bac et al. Tetrahedron Lett. 1988,29, 2819; Ma et al. J. Org. Chem. 2001, 66, 4525; Kato et al. J.Fluorine Chem. 99, 1, 1999, 5-8.

With respect to further details on the synthesis of the compoundsaccording to the invention, reference is additionally made to thefollowing in their full scope: WO2002/090317, WO2002/90330,WO2003/008370, WO2003/008731, WO2003/080557, WO2004/043899,WO2004/043900, WO2004/043902, WO2004/043909, WO2004/043949,WO2004/043967, WO2005/063769, WO2005/066183, WO2005/110970,WO2005/110971, WO2005/110973, WO2005/110974, WO2005/110975,WO2005/110976, WO2005/110977, WO2006/018184, WO2006/108565,WO2007/079927, WO2007/079928, WO2007/079930, WO2007/079931,WO2007/124903, WO2008/009415 and WO2008/009416.

EXAMPLES

The following examples serve to explain the invention in more detail,while not restricting it.

The yields of the compounds produced are not optimised. All temperaturesare uncorrected. The term “ether” means diethyl ether, “EE” ethylacetate and “DCM” dichloromethane. The term “equivalents” meanssubstance amount equivalents, “mp” melting point or melting range,“decomp.” decomposition, “RT” room temperature, “abs.” absolute (freefrom water), “rac.” racemic, “conc.” concentrated, “min” minutes, “h”hours, “d” days, “% vol.” percent by volume, “% m” percent by mass and“M” is a concentration detail in mol/l.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as thestationary phase for the column chromatography. The thin-filmchromatography tests were conducted with silica gel 60 F 254 HPTLCchromatoplates from E. Merck, Darmstadt. The mixture ratios of mobilesolvents for chromatography tests are always given in volume/volume.

Example 11-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diaminebis(2-hydroxypropane-1,2,3-tricarboxylate) a)1,4-bis-dimethylamino-4-phenylcyclohexane carbonitrile

A mixture of methanol (50 ml) and water (50 ml) was acidified withhydrochloric acid (37%, 0.2 ml) and mixed with an aqueous solution ofdimethylamine (40%, 11.5 ml, 91 mmol) with ice cooling and stirring.Then 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) and KCN(1.6 g, 24.6 mmol) were added to the solution. A clear solution wasformed after 15 min. The ice cooling was removed and the batch stirredfor 2.5 h at RT, and a white solid began to separate out after approx. 1h. The batch was brought to approx. 0° C. again for 1 h by means of icecooling to complete the precipitation. The precipitate was thenseparated by means of a fritted glass filter and dried in a vacuum at abath temperature of 40° C. A diastereoisomer mixture of the titlecompound was obtained with a yield of 1.83 g (67%) and a melting pointof 82-92° C.

13C NMR (101 MHz, CDCl3) δ ppm: 29.3*, 30.2, 31.2, 37.7, 38.2, 39.9,58.4*, 60.2, 62.4*, 118.7, 119.0, 126.8, 127.4, 127.7, 128.0, 136.2*,137.7* *spread signals

b)1-[imino-(1-methyl-1H-indol-2-yl)methyl]-N,N,N′,N′-tetramethyl-4-phenyl-cyclohexane-1,4-diamine[more non-polar diastereoisomer and more polar diastereoisomer]

N-methyl indole [1.31 g, 10 mmol dissolved in dry THF (10 ml)] was addedto a solution of n-butyl lithium (2.5N in n-hexane, 4 ml, 10 mmol) indry THF (10 ml) with the exclusion of moisture at 0° C. The batch wasstirred for 60 min while maintaining the cooling, and a solid began toprecipitate out after approx. 10 min. The addition of thediastereoisomer mixture from the previous step [1.33 g, 5 mmol,dissolved in dry THF (10 ml)] then occurred within 10 min. After theaddition had ended the cooling was removed and the batch stirred afurther 18 h after RT was reached. For work up the batch was carefullymixed with a mixture of THF (5 ml) and water (1 ml). Then, saturatedNaCl solution (30 ml) was added to the mixture. The organic phase wasseparated, the aqueous phase was extracted with ethyl acetate (4×20 ml).The combined organic extracts were dried over MgSO₄ and thenconcentrated to low volume. The residue obtained (2.7 g) was purified bychromatography [silica gel 60 G (10 g); ethyl acetate (100 ml), ethylacetate/ethanol 1:1 (100 ml), EtOH 50 ml]. The more non-polardiastereoisomer was thus obtained with a yield of 26% (526 mg) and themore polar diastereoisomer with a yield of 32% (650 mg).

c)1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diaminebis(2-hydroxypropane-1,2,3-tricarboxylate)

The more non-polar diastereoisomer (230 mg, 0.61 mmol) was dissolved inpropan-2-ol (5 ml) in the boiling heat and mixed with a hot solution ofcitric acid [382 mg, 2 mmol, in propan-2-ol (4 ml)]. A precipitate wasseparated out when the solution cooled to RT. The batch was left for 20h at 5° C. to complete the precipitation, then the solid was separatedby means of a fritted glass filter and dried. The bis-citrate was thusobtained as a vitreous solid with a yield of 310 mg (64%).

13C NMR (101 MHz, DMSO-D6) δ ppm: 25.5 (propan-2-ol), 26.9, 27.4, 30.9,37.5, 38.1, 43.3, 62.0 (propan-2-ol), 62.7, 66.1*, 71.9, 101.3*, 110.1,119.7, 120.7, 122.1, 126.3, 128.6, 128.8, 132.1*, 137.0, 137.3, 171.2,173.5, 175.5 *widely spread signals

Example 2(4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)-(1-methyl-1H-indol-2-yl)methanone(more non-polar diastereoisomer)

During the synthesis of the exemplary compound 6, step b) the analogousnon-polar compound was also formed as a mixture, this (680 mg) was mixedwith 2N HCl (20 ml) and stirred for 18 h at RT. A solid separated out.For work up the reaction mixture was basified with 2N NaOH (30 ml) atroom temperature. The aqueous phase was extracted with ethyl acetate(3×10 ml). The combined organic extracts were dried over MgSO₄ and thenconcentrated to low volume. Attempts to recrystallise the raw productformed (from ethyl acetate and DMSO) did not result in a separation ofthe impurity. A part of the raw product obtained was purified bychromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 2:8(100 ml)]. The title compound with a melting point of 212-218° C. wasthus isolated in an amount of 59 mg.

13C NMR (101 MHz, CDCl₃) δ ppm: 24.6, 26.4*, 29.9, 32.3, 37.9, 45.6,59.9* 67.6, 110.1, 110.6, 120.3, 122.7, 124.9, 125.8, 126.5, 127.3,127.6, 134.4, 138.2*, 138.9, 198.2 *spread signals

Example 31-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diaminebis(2-hydroxypropane-1,2,3-tricarboxylate) (more polar diastereoisomer)

The more polar diastereoisomer from Example 1, step b) (248 mg, 0.66mmol) was dissolved in propan-2-ol (5 ml) in the boiling heat and mixedwith a hot solution of citric acid [382 mg, 2 mmol, in hot propan-2-ol(4 ml)]. A precipitate was separated out when the solution cooled to RT.The batch was left for 20 h at 5° C. to complete the precipitation, thenthe solid was separated by means of a fritted glass filter and dried.The citrate was thus obtained as bis-citrate with a yield of 380 mg(73%, melting point from 80° C.).

13C NMR (101 MHz, DMSO-D6) δ ppm: 24.0, 25.4 (propan-2-ol), 28.1, 31.4,37.4, 37.5, 43.4, 62.0, 64.4 (propan-2-ol), 67.8, 71.8, 103.4, 110.2,119.7, 121.0, 122.4, 126.2, 128.8, 129.2, 129.3, 130.2, 136.2, 137.8,170.9, 171.2, 175.6

Example 4(1,4-bis-dimethylamino-4-phenylcyclohexyl)-(1-methyl-1H-indol-2-yl)-methanone(more non-polar diastereoisomer)

The exemplary compound 1 (250 mg, 0.62 mmol) was mixed with 2N HCl (10ml) and stirred for 3 h at RT and for 1 h at 50° C. (bath temperature).A precipitate separated out during the reaction time. For work up thereaction mixture was firstly neutralised with K₂CO₃ at room temperatureand then strongly basified with 2N NaOH (1 ml). The aqueous phase wasextracted with ethyl acetate (3×10 ml). The combined organic extractswere dried over MgSO₄ and then concentrated to low volume. The residueobtained (240 mg) was purified by chromatography [silica gel 60 G (10g); cyclohexane/ethyl acetate 1:1, (100 ml)]. The title compound wasthus separated from the starting product still present and obtained witha yield of 120 mg (48%) with a melting point of 165-169° C. (afterre-crystallisation from ethanol).

13C NMR (101 MHz, CDCl3) δ ppm: 24.2, 30.2, 32.3, 37.9, 38.8, 59.0,69.6, 110.1, 111.5, 120.3, 122.9, 125.0, 125.8, 126.3, 126.8, 127.4,134.8, 139.0, 139.3, 198.9

Example 5(1,4-bis-dimethylamino-4-phenylcyclohexyl)-(1-methyl-1H-indol-2-yl)-methanone(more polar diastereoisomer)

The exemplary compound 3 (360 mg, 0.9 mmol) was mixed with 2N HCl (10ml) and stirred for 4 h at 70° C. (bath temperature). For work up thereaction mixture was firstly neutralised with K₂CO₃ at room temperatureand then strongly basified with 2N NaOH (1 ml). The aqueous solution wasextracted with ethyl acetate (3×10 ml). The combined organic extractswere dried over MgSO₄ and then concentrated to low volume. The residueobtained (240 mg) was purified by chromatography [silica gel 60 G (10g); cyclohexane/ethyl acetate 1:1, (150 ml), ethyl acetate (50 ml)]. Thetitle compound was thus isolated with a yield of 234 mg (65%) with amelting point of 109-111° C. (after re-crystallisation frompropan-2-ol).

13C NMR (101 MHz, CDCl₃) δ ppm: 25.2, 29.8, 32.5, 38.3, 38.5, 61.8,69.7, 110.2, 111.7, 120.3, 122.9, 125.1, 125.8, 126.5, 127.8, 127.9,133.7, 136.8, 139.2, 198.4

Example 64-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine(more polar diastereoisomer) a)4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexane carbonitrile

A mixture of methanol (50 ml) and water (50 ml) was acidified withhydrochloric acid (37%, 0.2 ml) and mixed with pyrrolidine (7.5 ml, 91mmol) with ice cooling and stirring.4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) was then addedto the solution. The batch was stirred for 10 min to dissolve the ketoneas completely as possible. KCN (1.6 g, 24.6 mmol) was then added. Theice cooling was removed and the batch stirred for 2 d at RT, duringwhich white solid separated out. The batch was brought to approx. 0° C.again for 1 h by ice cooling to complete the precipitation. Theprecipitate was then separated by means of a fritted glass filter anddried in a vacuum at a bath temperature of 40° C. A diastereoisomermixture of the title compound was obtained with a yield of 2.7 g (90%)and with a melting point of 136-142° C.

AS 09460: 13C NMR (101 MHz, CDCl₃) δ ppm: 23.4, 23.5, 29.1*, 31.4,32.3*, 37.7, 38.2, 48.0, 48.1, 58.8*, 60.3*, 61.8*. 62.2*, 119.7, 120.0,126.7, 126.8, 127.4, 127.7, 127.9, 136.4*, 137.5* *spread signals

b)4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine(more polar diastereoisomer)

N-methyl indole [1.31 g, 10 mmol, dissolved in dry THF (10 ml)] wasadded to a solution of n-butyl lithium (2.5N in n-hexane, 4 ml, 10 mmol)in dry THF (10 ml) with exclusion of moisture at 0° C. The batch wasstirred for 60 min while maintaining the cooling, and a solid began toseparate out after approx. 10 min. The diastereoisomer mixture from theprevious step [1.49 g, 5 mmol, dissolved in dry THF (20 ml)] was thenadded within 20 min. After the addition had ended the cooling wasremoved and the batch stirred a further 18 h after RT was reached. Forwork up the batch was carefully mixed with a mixture of THF (5 ml) andwater (1 ml). Then saturated NaCl solution (30 ml) was added to themixture. The organic phase was separated, the aqueous phase wasextracted with ethyl acetate (4×20 ml). The combined organic extractswere dried over MgSO₄ and then concentrated to low volume. The residueobtained (2.78 g) was purified by chromatography [silica gel 60 G (10g); ethyl acetate (200 ml), ethyl acetate/ethanol 1:1 (50 ml)]. The morepolar diastereoisomer could thus be isolated as a viscous mass with ayield of 6% (140 mg). The non-polar diastereomer was obtained as amixture.

13C NMR (101 MHz, CDCl₃) δ ppm: 24.2, 26.0, 29.8, 31.7, 38.2, 44.9,61.3, 64.2, 104.9, 109.8, 119.9, 121.4, 122.7, 126.5, 127.0, 127.6,127.7, 137.0, 137.3, 138.3, 175.2

Example 7(4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)-(1-methyl-1H-indol-2-yl)methanone(more polar diastereoisomer)

Exemplary compound 6, step b) (99 mg, 0.23 mmol) was mixed with 2N HCl(3 ml) and stirred for 18 h at RT. The solution turned orange in colourimmediately after the acid was added. For work up the reaction mixturewas basified with 2N NaOH (5 ml) at room temperature. The aqueous phasewas extracted with dichloromethane (3×10 ml). The combined organicextracts were dried over MgSO₄ and then concentrated to low volume. Theresidue obtained (84 mg) was purified by chromatography [silica gel 60 G(10 g); ethyl acetate (120 ml)]. The title compound was thus isolatedwith a yield of 68 mg (68%) and a melting point from 134° C.

13C NMR (101 MHz, CDCl3) δ ppm: 24.1, 26.3*, 29.9, 32.4, 38.3, 45.3,61.6*, 67.9, 110.2, 111.1, 120.3, 122.9, 125.0, 125.9, 126.5, 127.8,127.9, 134.1, 136.9*, 139.1, 198.1 *spread signals

Example 8 N,N,N′-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine(non-polar diastereomer) a)4-dimethylamino-1-methylamino-4-phenyl-cyclohexane carbonitrile

40% aqueous methylamine solution (8.7 mL, 69 mmol) and4-dimethylamino-4-phenylcyclohexanone (3.13 g, 14.4 mmol) dissolved inmethanol (15 mL) were added to a solution of 4N hydrochloric acid (3.75mL) and methanol (2.25 mL) cooled to 0° C. The reaction mixture was thenmixed with potassium cyanide (2.25 g, 34 mmol) and stirred for 5 d atRT. For work up the mixture was mixed with water (60 mL) and extractedwith ether (3×50 ml). The combined organic phases were dried with sodiumsulphate and concentrated to low volume in a vacuum.

Yield: 3.48 g (94%), diastereomer mixture

1H-NMR (DMSO-d6): 1.31 (1H, m); 1.64 (1H, m); 1.79 (2H, m); 1.93 (6H,d); 2.03 (2H, m); 2.22 and 2.34 (3H, dd); 2.77 (1H, m); 2.63 and 2.77(1H, m); 7.33 (5H, m).

b) N,N,N′-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (non-polardiastereomer)

Phenyl lithium (8.4 mL, 15 mmol, 1.8 M solution in dibutyl ether) wasprovided in argon and Mixed drop by drop with a solution of thediastereoisomer mixture from the previous step (1.29 g, 5 mmol) indiethyl ether (15 mL) at RT. During this, the temperature of thereaction mixture increased to 35° C. and a solid separated out. Thereaction mixture was boiled for 30 min with reflux (bath 50° C.), thenhydrolysed in an ice bath (0-10° C.) with 20% NH₄Cl solution (10 mL) andthe organic phase separated. The aqueous phase was extracted with ether(2×30 mL). The combined organic solutions were dried over Na₂SO₄ andconcentrated to low volume in a vacuum.

The residue was separated by flash chromatography (50 g silica gel) withchloroform/methanol (20:1→9:1→1:1+1% TEA).

Yield: 283 mg (18%) non-polar diastereomer, oil

1H-NMR (DMSO-d6): 1.64 (2H, m); 1.86 (3H, s); 1.92 (6H, s); 2.09 (6H,m); 7.25 (2H, m); 7.35 (6H, m); 7.49 (2H, m).

Example 9 N,N,N′-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (polardiastereomer)

The analogous polar diastereomer could also be isolated during thepurification of the exemplary compound 8 step b).

Yield: 306 mg (20%) polar diastereomer.

1H-NMR (DMSO-d6): 1.47 (2H, m); 1.87 (5H, m); 1.95 (6H, s); 2.13 (4H,m); 7.10 (1H, m); 7.23 (5H, m); 7.34 (4H, m).

Example 10 N,N,N′,N′-tetramethyl-1,4-diphenyl-cyclohexane-1,4-diamine(non-polar diastereomer)

A solution of the exemplary compound 8 (242 mg, 0.78 mmol) and formalin(1.1 mL, 37% aqueous solution) in acetonitrile (10 mL) was mixed inportions with sodium cyanoboron hydride (200 mg, 3.2 mmol) and stirredfor 45 min at RT. Conc. acetic acid was then added until a neutralreaction occurred and was stirred for 45 min at RT. For work up thesolvent was removed in a vacuum, the residue taken up in 2N NaOH (10 mL)and then extracted with ether (3×10 mL). The organic solution was driedover Na₂SO₄ and concentrated to low volume in a vacuum. The remainingresidue was purified by flash chromatography with CHCl₃/MeOH (1:1).

Yield: 230 mg (92%)

Melting point: 117-118° C.

1H-NMR (DMSO-d6): 1.76 (4H, wide); 1.96 (12H, s); 2.28 (4H, wide); 7.15(2H, m); 7.27 (8H, m).

Example 11 N,N,N′,N′-tetramethyl-1,4-diphenyl-cyclohexane-1,4-diamine(polar diastereomer)

A solution of the exemplary compound 9, step b) (223 mg, 0.72 mmol) andformalin (1.0 mL, 37% aqueous solution) in acetonitrile (10 mL) wasmixed in portions with sodium cyanoboron hydride (182 mg, 2.9 mmol) andstirred for 45 min at RT. Conc. acetic acid was then added until aneutral reaction occurred and was stirred for 45 min at RT. For work upthe solvent was removed in a vacuum, the residue was taken up in 2N NaOH(10 mL) and then extracted with ether (3×10 mL). The organic solutionwas dried over Na₂SO₄ and concentrated to low volume in a vacuum. Theremaining residue was purified by flash chromatography with CHCl₃/MeOH(9:1).

Yield: 160 mg (69%)

Melting point: 197-198° C.

1H-NMR (CD3OD): 1.47 (4H, d); 1.91 (12H, s); 2.75 (4H, d); 7.32 (2H, m);7.46 (8H, m).

Example 121-benzyl-N,N,N′,N′-tetramethyl-4-phenyl-cyclohexane-1,4-diamine(non-polar diastereomer) a) 1,4-bis-dimethylamino-4-phenyl-cyclohexanecarbonitrile

40% aqueous dimethylamine solution (14 mL, 110.5 mmol),4-dimethylamino-4-phenyl-cyclohexanone (5.00 g, 23.04 mmol) andpotassium cyanide (3.60 g, 55.3 mmol) were added to a mixture of 4Nhydrochloric acid (14 mL) and methanol (5 mL) with ice cooling. Themixture was stirred for 2 d at room temperature and then after addingwater (200 mL) was extracted with ether (4×150 mL). After the solutionwas concentrated to low volume, the residue was taken up indichloromethane (200 mL) and dried with magnesium sulphate overnight,filtered and the solvent removed in a vacuum. The nitrile was obtainedas an oil which was crystallised through.

Yield: 5.87 g (90%)

1H-NMR (DMSO-d6): 1.36 (1H, m); 1.61 (1H, m); 1.61 (2H, m); 1.92 (8H,m); 2.16 (4H, m); 2.28 (3H, s); 2.44 (1H, m); 2.59 (1H, m); 7.35 (5H,m).

b) 1-benzyl-N,N,N′,N′-tetramethyl-4-phenyl-cyclohexane-1,4-diamine(non-polar diastereomer)

The title compound of the previous step (5.84 g, 20.5 mmol) wasdissolved in THF (115 mL) and mixed in drops with benzyl magnesiumchloride 2M (36 mL, 71.57 mmol) with ice cooling. The reaction mixturewas stirred overnight at room temperature. The reaction mixture wasmixed with 20% ammonium chloride solution (15 mL) and water (10 mL) andextracted with diethyl ether (3×50 mL). The combined organic phases werewashed with water (50 mL) and saturated NaCl solution (50 mL), driedover Na₂SO₄, filtered and concentrated to low volume in vacuum.

The residue was purified by flash chromatography with cyclohexane/ethylacetate (1:1).

Yield: 770 mg (11%) non-polar diastereomer

1H-NMR (DMSO-d6): 1.57 (4H, m); 1.72 (2H, m); 1.79 (6H, s); 2.19 (6H,s); 2.23 (2H, m); 2.63 (2H, s); 7.26 (10H, m).

Example 131-benzyl-N,N,N′,N′-tetramethyl-4-phenyl-cyclohexane-1,4-diamine (polardiastereomer)

The analogous polar diastereomer could also be isolated during thepurification of the exemplary compound 12 step b).

The residue was purified by flash chromatography with cyclohexane/ethylacetate (1:1). The non-polar diastereomer was obtained in clean state.The polar diastereomer was isolated in impure state and once againpurified by flash chromatography with acetonitrile/methanol/1N NH₄Cl(9:1:1).

Yield: 600 mg (9%) polar diastereomer

1H-NMR (DMSO-d6): 0.88 (2H, t); 1.70 (2H, m); 1.85 (6H, s); 1.90 (2H,m); 2.14 (2H, m); 2.26 (6H, s); 2.48 (2H, s); 7. 00 (6H, m); 7.18 (4H,m).

13C-NMR (DMSO-d6): 27.1; 28.6; 36.3; 36.8; 37.8; 57.0; 60.5; 125.2;125.8; 127.1; 127.2; 130.2; 136.9; 138.7.

Example 144-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine2-hydroxypropane-1,2,3-tricarboxylate a)[4-methoxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

Methyl propargyl ether (1.47 g, 21.0 mmol) dissolved in abs. THF (15 mL)was added in drops to a 2.5 M solution of butyl lithium in hexane (8.4mL, 21.0 mmol) at −30° C. in argon. A solution of4-dimethylamino-4-phenylcyclohexanone (4.34 g, 20.0 mmol) in abs. THF(20 mL) and lithium bromide (0.87 g, 10 mmol) dissolved in abs. THF (2.5mL) was then added at −30° C. The reaction mixture was heated to −5° C.,mixed drop by drop with a solution of methyl iodide (4.25 g, 30 mmol) inabs. DMSO (25 mL) and stirred for 2 h at 50° C. For work up of thereaction mixture water (30 mL) was added with ice bath cooling andextracted with cyclohexane (4×50 mL). The organic phase was washed with20% ammonium chloride solution, dried over Na₂SO₄ and concentrated tolow volume in a vacuum. The remaining residue was purified by flashchromatography with CHCl₃/MeOH (20:1).

Yield: 2.34 g (39%)

1H-NMR (DMSO-d6): 1.57 (2H, m); 1.96 (10H, m); 2.25 (2H, m); 3.18 (3H,s); 3.27 (3H, m); 4.05 (2H, s); 7.37 (5H, m).

b)[4-Methoxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

2-iodoaniline (328 mg, 1.5 mmol), the title compound of the previousstep (452 mg, 1.5 mmol) and sodium carbonate (795 mg, 7.5 mmol) weredissolved in abs. DMF (10 mL) in argon. The catalyst (PEPPSI®, 204 mg,0.3 mmol) was then added and the solution stirred for 24 h at 100° C.For work up the black reaction solution was concentrated in a vacuumuntil dry, the residue was dissolved in CHCl₃ and washed with water. Theorganic phase was dried over Na₂SO₄ and concentrated to low volume in avacuum. The remaining residue was purified by flash chromatography withCHCl₃/MeOH (20:1→9:1).

Yield: 71 mg (12%)

1H-NMR (DMSO-d6): 1.62 (2H, m); 2.22 (10H, m); 2.63 (2H, m); 3.00 (3H,s); 3.10 (3H, m); 4.46 (2H, s); 6.95 (2H, m); 7.28 (1H, d); 7.46 (6H;m); 10.72 (1H, s).

c)4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine2-hydroxypropane-1,2,3-tricarboxylate

The title compound of the previous step (217 mg, 0.55 mmol) wasdissolved in hot ethanol (4 mL) and mixed with a solution of citric acid(106 mg, 0.55 mmol) in hot ethanol (2 mL). After standing for 2 h in therefrigerator and adding ether, the solid formed was aspirated and driedin a vacuum.

Yield: 165 mg (51%)

Melting point: 184-186° C.

1H-NMR (DMSO-d6): 1.61 (2H, m); 2.22 (4H, m); 2.37 (6H, s); 2.52 (4H,m); 3.01 (3H, s); 3.08 (3H, m); 4.45 (2H, s); 6.99 (2H, m); 7.25 (1H,d); 7.50 (4H, m); 7.65 (2H, m); 10.73 (1H, s).

Example 154-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanaminea)[4-benzyloxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

Methyl propargyl ether (0.36 g, 5.2 mmol) dissolved in abs. THF (5 mL)was added in drops to a 2.5 M solution of butyl lithium in hexane (2.1mL, 5.2 mmol) at −30° C. in argon. A solution of4-dimethylamino-4-phenylcyclohexanone (1.08 g, 5.0 mmol) in abs. THF (5mL) and lithium bromide (0.22 g, 2.5 mmol) dissolved in abs. THF (2.0mL) was then added at −30° C. The reaction mixture was heated to −5° C.,mixed in drops with a solution of benzyl bromide (1.28 g, 7.5 mmol) inabs. DMSO (10 mL) and stirred 2 h at 50° C. For work up of the reactionmixture water (10 mL) was added with ice bath cooling and extracted withcyclohexane (4×20 mL). The organic phase was washed with 20% ammoniumchloride solution, dried over Na₂SO₄ and concentrated to low volume in avacuum. The remaining residue was purified by flash chromatography withCHCl₃/MeOH (40:1).

Yield: 541 g (29%), non-polar compound

1H-NMR (DMSO-d6): 1.67 (2H, m); 1.94 (6H, s); 2.04 (4H, m); 2.30 (2H,m); 3.19 (3H, s); 4.09 (2H, s); 4.60 (2H, s); 7.31 (10H, m).

b)4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine

2-acetylamino-iodoaniline (359 mg, 1.37 mmol), the title compound of theprevious step (519 mg, 1.37 mmol) and sodium carbonate (726 mg, 6.85mmol) were dissolved in abs. DMF (10 mL) in argon. The catalyst (PEPPSI,190 mg, 0.28 mmol) was then added and the solution stirred for 24 h at100° C. For work up the black reaction solution was concentrated in avacuum until dry, the residue dissolved in CHCl₃ and washed with water.The organic phase was dried over Na₂SO₄ and concentrated to low volumein a vacuum. The remaining residue was purified by flash chromatographywith CHCl₃/MeOH (50:1).

Yield: 210 mg (33%)

1H-NMR (DMSO-d6): 1.67 (2H, m); 1.61 (2H, m); 2.10 (6H, bs); 2.38 (2H,m); 2.70 (2H, m); 3.11 (3H, s); 4.13 (2H, s); 4.57 (2H, s); 7.02 (2H,m); 7.30 (12H, m); 10.78 (1H, s).

Example 164-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine2-hydroxy propane-1,2,3-tricarboxylate a)[4-ethoxy-4-(3-methoxy-prop-1-ynyl)-1-phenyl-cyclohexyl]-dimethylamine

Methyl propargyl ether (1.47 g, 21.0 mmol) dissolved in abs. THF (15 mL)was added in drops to a 2.5 M solution of butyl lithium in hexane (8.4mL, 21.0 mmol) at −30° C. in argon. A solution of4-dimethylamino-4-phenylcyclohexanone (4.34 g, 20.0 mmol) in abs. THF(20 mL) and lithium bromide (0.87 g, 10 mmol) dissolved in abs. THF (2.5mL) was then added at −30° C. The reaction mixture was heated to −5° C.,mixed in drops with a solution of ethyl iodide (4.68 g, 30 mmol) in abs.DMSO (30 mL) and stirred for 2 h at 50° C. For work up of the reactionmixture water (30 mL) was added with ice bath cooling and extracted withcyclohexane (4×50 mL). The organic phase was washed with 20% ammoniumchloride solution, dried over Na₂SO₄ and concentrated to low volume in avacuum. The remaining residue was purified by flash chromatography withCHCl₃/MeOH (20:1).

Yield: 3.92 g (62%)

1H-NMR (DMSO-d6): 1.12 (3H, t); 1.58 (2H, m); 1.96 (10H, m); 2.25 (2H,m); 3.17 (3H, s); 3.51 (2H, q); 4.04 (2H, s); 7.37 (5H, m)

b)[4-ethoxy-4-(3-methoxymethyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine

N-(2-iodo-phenyl)-acetamide (522 mg, 2.0 mmol), the title compound ofthe previous step (631 mg, 2.0 mmol) and sodium carbonate (1.06 g, 10.0mmol) were dissolved in abs. DMF (10 mL) in argon. The catalyst (PEPPSI,272 mg, 0.4 mmol) was then added and the solution stirred for 24 h at100° C. For work up the black reaction solution was concentrated in avacuum until dry, the residue dissolved in CHCl₃ and washed with water.The organic phase was dried over Na₂SO₄ and concentrated to low volumein a vacuum. The remaining residue was purified by flash chromatographywith CHCl₃/MeOH (50:1).

Yield: 249 mg (31%)

1H-NMR (DMSO-d6): 1.11 (3H, t); 1.61 (2H, m); 1.99 (8H, m); 2.19 (2H,m); 2.48 (2H, m); 3.12 (5H, m); 4.53 (2H, s); 6.99 (2H, m); 7.27 (2H,d); 7.47 (5H, m); 10.61 (1H, s).

c)4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine2-hydroxypropane-1,2,3-tricarboxylate

The title compound of the previous step (188 mg, 0.462 mmol) wasdissolved in hot ethanol (4 mL) and mixed with a solution of citric acid(89 mg, 0.462 mmol) in hot ethanol (2 mL). After standing for 2 h in therefrigerator and adding ether, the solid formed was aspirated and driedin a vacuum.

Yield: 152 mg (55%)

Melting point: 166-167° C.

1H-NMR (DMSO-d6): 1.12 (3H, t); 1.57 (2H, m); 2.17-2.35 (10H, m); 2.58(4H, m); 2.70 (2H, m); 3.11 (3H, m); 4.51 (2H, s); 6.98 (2H, m); 7.24(2H, d); 7.43 (4H, m); 7.62 (2H, m); 10.67 (1H, s).

Example 17N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)acetamide2-hydroxypropane-1,2,3-tricarboxy late a)dimethyl-(4-methylene-1-phenyl-cyclohexyl)-amine

Tert-BuOK (0.550 g, 4.74 mmol) was provided in abs. ether (10 mL) inargon and methyl triphenyl phosphonium bromide (1.89 g, 4.74 mmol)added. The mixture was then heated to 40° C. for 30 min. After thisreaction time 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.60 mmol)dissolved in abs. THF (10 mL) was carefully added in drops and thereaction solution was heated to 50° C. for 5 h. The reaction batch wasstirred overnight at room temperature and concentrated in a vacuum untildry. The residue was taken up in dioxan (50 mL) and mixed withHCl/dioxan (5 mL). The precipitated solid was aspirated and washed withether. The isolated hydrochloride was basified with 2 N NaOH andextracted with dichloromethane (2×80 mL). The organic phase was driedover Na₂SO₄, filtered and concentrated to low volume in a vacuum.

Yield: 0.86 g (61%)

1H-NMR (DMSO-d6): 1.82 (2H, m); 1.99 (2H, m); 2.30 (2H, m); 2.43 (6H,d); 3.01 (2H, m); 4.67 (2H, s); 7.55 (3H, m); 7.72 (2H, m).

b) 4-dimethylamino-1-methyl-4-phenyl-cyclohexane carbonitrile

R—R-cobalt(II)-salen complex (Jacobsen's ligand, 26.0 mg, 0.04 mmol) wasdissolved in dichloromethane (5 mL), mixed with acetic acid (29 μL, 0.08mmol, 2 eq.) and stirred in an open flask for 30 min. The batch was thenconcentrated to low volume in a vacuum and the excess acetic acid wasazeotropically removed with toluol. The cobalt(III) catalyst producedwas provided in abs. ethanol (5 mL) in argon. After 2 min the titlecompound of the previous step (0.860, 3.99 mmol) dissolved in ethanol (8mL), p-toluol sulphonyl cyanide (714 mg, 5.58 mmol) were added followedby phenyl silane (0.49 mL, 3.99 mmol). Ethanol (5 mL) was then addedonce again and the reaction solution was stirred for 3 d at roomtemperature. The batch was concentrated in a vacuum until dry and theresidue purified by flash chromatography (2× on normal silica gel and 1×on ultrafine silica gel) with ethyl acetate. Further studies have shownthat a single purification by column chromatography on ultrafine silicagel with chloroform/methanol (20:1) was sufficient.

Yield: 0.130 g, (13%)

1H-NMR (DMSO-d6): 1.09 (2H, m); 1.16 (3H, s); 1.78 (2H, m); 1.87 (2H,m); 1.92 (6H, s); 2.56 (2H, m); 7.32 (5H, m).

13C-NMR (DMSO-d6): 25.4; 29.8; 33.1; 33.7; 37.8; 60.3; 124.5; 126.5;127.5; 127.7; 135.4.

c) (4-aminomethyl-4-methyl-1-phenyl-cyclohexyl)-dimethylamine

LiAlH₄ (38.0 mg, 0.81 mmol) was provided in abs. THF (5 mL) in argon,slowly mixed with the title compound of the previous step (0.130 g, 0.54mmol) dissolved in abs. THF (5 mL) and the reaction mixture stirred for3 h with reflux. THF (10 mL) and water (4 mL) were then added with icecooling and the mixture stirred again for 30 min. The precipitate wasfiltered off over celite and washed with dichloromethane (50 mL). Thefiltrate was concentrated in a vacuum until dry.

Yield: 0.12 g (90%)

1H-NMR (DMSO-d6): 0.72 (3H, s); 0.99 (2H, m); 1.13 (2H, t, NH2); 1.50(2H, m); 1.84 (2H, m); 1.90 (6H, s); 2.04 (2H, m); 2.39 (2H, t); 7.24(5H, m).

d) N-(4-dimethylamino-1-methyl-4-phenyl-cyclohexylmethyl)-acetamide

The title compound of the previous step (0.120 g, 0.48 mmol) wasdissolved in abs. THF (2.5 mL) and mixed with triethylamine (72.0 μL,0.53 mmol) and acetyl chloride (42.0 mg, 38.0 μl, 0.53 mmol). Thereaction mixture was stirred for 16 h at room temperature. The batch wasconcentrated in a vacuum until dry, the residue taken up in ethylacetate (10 mL) and washed with saturated NaHCO₃ solution (2×10 mL) andwith saturated NaCl solution. The organic phase was dried over Na₂SO₄,filtered and concentrated to low volume in a vacuum.

Yield: 109 mg (77%)

1H-NMR (DMSO-d6): 0.71 (3H, s); 0.96 (2H, m); 1.17 (2H, m); 1.47 (2H,m); 1.84 (3H, s); 1.91 (6H, s); 2.11 (2H, m); 3.02 (2H, d) 7.30 (5H, m);7.69 (1H, t).

e) N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)acetamide2-hydroxypropane-1,2,3-tricarboxylate

The title compound of the previous step (102 mg, 0.35 mmol) wasdissolved in hot ethanol (4 mL). Citric acid (67.0 mg, 0.35 mmol) wasdissolved in hot ethanol (1.0 mL) and added. The batch was subsequentlystirred for 2 h at room temperature. Since no precipitate separated out,the solution was concentrated to low volume in a vacuum. The residue hadether stirred through it, was concentrated once again in a vacuum andthen dried in a vacuum. The desired citrate was obtained as a poroussolid.

Yield: 167 mg (98%)

1H-NMR (DMSO-d6): 0.62 (3H, s); 0.92 (2H, m); 1.45 (2H, m); 1.83 (3H,s); 2.07-2.60 (14H, m); 3.07 (2H, d) 7.46 (5H, m); 7.72 (1H, t).

Example 184-chloro-N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzolsulphonamide 2-hydroxypropane-1,2,3-tricarboxylate a)4-chloro-N-(4-dimethylamino-1-methyl-4-phenyl-cyclohexylmethyl)-benzolsulphonamide

The title compound from Example 17, step c) (0.160 g, 0.65 mmol) wasdissolved in abs. THF (3.4 mL), mixed with triethylamine (97 μL, 0.714mmol) and 4-chlorobenzol sulphonic acid chloride (151 mg, 0.71 mmol) andstirred for 1 d at room temperature. The batch was concentrated in avacuum until dry and the residue purified by flash chromatography: 1stcolumn with ethyl acetate/ethanol (9:1) and 2nd column with ethylacetate.

Yield: 70 mg (26%)

1H-NMR (DMSO-d6): very poor spectrum resolution

b)4-chloro-N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzolsulphonamide 2-hydroxypropane-1,2,3-tricarboxylate

The title compound of the previous step (0.070 g, 0.17 mmol) wasdissolved in hot isopropanol (4 mL). Citric acid (32.0 mg, 0.17 mmol)was dissolved in hot isopropanol (1.0 mL) and added. The batch wasstirred for 2 h at room temperature. Since no precipitate separated out,the solution was concentrated to low volume in a vacuum. The residue hadether stirred through it, was concentrated once again in a vacuum andthen dried in a vacuum. The desired citrate was obtained as a poroussolid.

Yield: 58 mg (57%)

1H-NMR (DMSO-d6): 0.64 (3H, m); 0.90-1.04 (6H, m); 1.54 (2H, m); 1.92(2H, m); 2.31 (6H, s); 2.73 (4H, m); 7.47-7.84 (5H, m); 10.8 (2H, wide).

Example 19N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzolsulphonamide 2-hydroxypropane-1,2,3-tricarboxylate a)(4-butylidene-1-phenyl-cyclohexyl)-dimethylamine

Potassium tert-butylate (2.75 g, 23.7 mmol) was provided in abs. ether(50 mL) in argon and mixed with butyl-triphenyl phosphonium bromide(9.45 g, 23.7 mmol). The batch was heated for 30 min to 40° C.4-dimethylamino-4-phenyl cyclohexanone (5.00 g, 23.0 mmol) dissolved inabs. THF (50 mL) was then added carefully in drops (exothermicreaction). The batch was heated for 6.5 h to 50° C. and stirredovernight at room temperature. The batch was then concentrated in avacuum until dry, taken up in dioxan (20 mL) and mixed with HCl/dioxan(5 mL). A precipitate separated out during this. This was filtered off,washed with ether (10 mL), then basified with 2N NaOH and extracted withdichloromethane (2×40 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated in a vacuum until dry.

Yield: 4.60 g (77%)

1H-NMR (DMSO-d6): 0.83 (3H, t); 1.27 (2H, m); 1.94 (9H, m); 2.09 (5H,m); 2.29 (2H, m); 5.04 (1H, t); 7.23 (1H, m); 7.36 (4H, m).

b) 1-butyl-4-dimethylamino-4-phenyl-cyclohexane carbonitrile

The cobalt(III) catalyst (297 mg, 0.456 mmol) was provided in abs.ethanol (100 mL) in argon. The title compound of the previous step (11.6g, 45.3 mmol) dissolved in ethanol (40 mL) was then added and p-toluolsulphonyl cyanide (13.0 g, 68.0 mmol), phenyl silane (5.6 mL, 45.3 mmol)and ethanol (10 mL) were then added. The temperature rose to 35° C. andtherefore the mixture was cooled with ice water. The batch was stirredfor 72 h at room temperature and then concentrated in a vacuum untildry. The residue was purified by flash chromatography withchloroform/methanol (20:1). The pre-purified substance was purifiedagain by MPLC column chromatography with chloroform/methanol (50:1,20:1).

Yield: 0.233 g (1.8%)

1H-NMR (DMSO-d6): 0.83 (3H, t); 1.08 (2H, m); 1.27 (6H, m); 1.75 (2H,m); 1.93 (8H, m); 2.63 (2H, m); 7.36 (5H, m).

c) (4-aminomethyl-4-butyl-1-phenyl-cyclohexyl)-dimethylamine

The title compound of the previous step (247 mg, 0.856 mmol) wasdissolved in abs. THF (5 mL). LiAlH₄ (64 mg, 1.71 mmol) was then addedin argon and the batch heated to boiling for 5.5 h. For work up THF (12mL) and H₂O (5 mL) were added to the batch and this was subsequentlystirred for 30 min. The batch was filtered via a fritted glass filterwith diatomaceous earth (2 cm), rinsed with dichloromethane (50 mL) andchloroform (50 mL) and concentrated to low volume in a vacuum. Theresidue was purified by flash chromatography with chloroform/methanol(20:1, 9:1, methanol).

Yield: 70 mg (28%)

1H-NMR (DMSO-d6): 0.80 (3H, t); 1.08 (9H, m); 1.45 (2H, m); 1.93 (10H,m); 2.45 (2H, m); 7.31 (5H, m).

d) N-(1-butyl-4-dimethylamino-4-phenyl-cyclohexylmethyl)-4-chlorobenzolsulphonamide

The title compound of the previous step (65.0 mg, 0.225 mmol) wasdissolved in abs. THF (5 mL) in argon and mixed with triethylamine (33.5μL, 0.247 mmol). 4-chlorobenzol sulphonic acid chloride (52.0 mg, 0.247mmol) was then added to the batch. The batch was stirred overnight atroom temperature. It was then concentrated in a vacuum until dry. Theresidue was taken up in ethyl acetate (10 mL) and washed with saturatedNaHCO₃ solution (2×10 mL) and with saturated NaCl solution (2×10 mL)solution. The organic phase was dried over Na₂SO₄, filtered andconcentrated in a vacuum until dry.

Yield: 103 mg (98%)

1H-NMR (DMSO-d6): 0.76 (3H, t); 0.97 (8H, m); 1.44 (2H, m); 1.87 (10H,m); 2.63 (2H, m); 7.35 (5H, m); 7.52 (1H, t); 7.68 (2H, m); 7.85 (2H,m).

e)N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzolsulphonamide 2-hydroxypropane-1,2,3-tricarboxylate

The title compound of the previous step (103 mg, 0.22 mmol) wasdissolved in hot ethanol (3 mL). Citric acid (42 mg, 0.22 mmol) wasdissolved in hot ethanol (1 mL) and added. The batch was cooled to roomtemperature and then concentrated in a vacuum until dry.

Yield: 128 mg (88%)

Melting point: porous solid?

1H-NMR (DMSO-d6): 0.86 (3H, t); 0.94 (6H, m); 1.10 (2H, m); 1.50 (2H,m); 1.86 (2H, m); 2.28 (6H, s); 2.51-2.64 (6H, m); 7.52 (6H, m); 7.72(2H, t); 7.87 (2H, m).

Example 20(−4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol(non-polar diastereoisomer) a) 1,4-dioxaspiro[4,5]decane-8-carboxylicacid ethyl ester

A solution of ethyl-4-oxocyclohexane carboxylate (28.9 g, 169 mmol),ethylene glycol (36.7 g, 33.0 mL, 592 mmol) and p-toluol sulphonic acid(380 mg, 2.0 mmol) in toluol (90 mL) was stirred overnight at roomtemperature. The reaction solution was poured into ether (150 mL) andwashed with water and 5% sodium hydrogencarbonate solution (150 mLeach). The organic phase was dried with sodium sulphate and concentratedto low volume in a vacuum. Since the raw product (26.8 g) was obtainedin pure form, it could be directly converted further.

Yield: 26.8 g (74%), colourless oil

b) 8-(4-phenylbutyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethylester

A 2.5 M solution of n-butyl lithium (2.5 g, 15.7 mL, 39.2 mmol) wasslowly added in drops to a solution of diisopropylamine (3.96 g, 5.50mL, 39.2 mmol) in absolute tetrahydrofuran (50 mL) at −78° C. in argon.1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone (DMPU, 10.0 g, 9.42 mL,78.2 mmol) and a solution of the title compound of the previous step(8.40 g, 39.2 mmol) in absolute tetrahydrofuran (30 mL) were added indrops one after the other to this mixture. The reaction solution wasfurther stirred for 2 h at this temperature before a solution of1-bromo-4-phenylbutane (10.0 g, 47.0 mmol) in absolute tetrahydrofuran(50 mL) was added in drops. The resulting solution was stirred overnightat room temperature. Saturated ammonium chloride solution (50 mL) wasthen added and extracted with ether (2×50 mL). The combined organicphases were washed with saturated sodium chloride solution (50 mL),dried with sodium sulphate and concentrated to low volume in a vacuum.The raw product (17.7 g) was purified by means of flash chromatography(400 g, 20×7.5 cm) with cyclohexane/ethyl acetate (9:1).

Yield: 10.3 g (76%), colourless oil

1H-NMR (DMSO-d6): 1.12 (t, 3H, J=7.1 Hz); 1.39-1.62 (m, 12H); 1.91-2.03(m, 2H); 2.54 (t, 2H, J=7.4 Hz); 3.82 (s, 4H); 4.05 (q, 2H, J=7.1 Hz);7.12-7.17 (m, 3H); 7.22-7.28 (m, 2H).

c) [8-(4-phenylbutyl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol

A solution of the title compound of the previous step (10.2 g, 33.5mmol) in absolute tetrahydrofuran (50 mL) was added in drops to asuspension of lithium aluminium hydride (2.50 g, 67.0 mmol) in absolutetetrahydrofuran (100 mL) in argon at 65° and stirred for 3 h at thistemperature, after which the conversion was complete. After cooling thereaction mixture was mixed with water (4.5 mL) and 4N sodium hydroxidesolution (1.1 mL) and filtered from the precipitate formed. The residuewas washed with tetrahydrofuran (2×60 mL) and the filtrate concentratedto low volume in a vacuum. Since the product was obtained in pure form,it could be directly converted further.

Yield: 9.44 g (93%), light yellow oil

1H-NMR (DMSO-d6): 1.14-1.32 (m, 6H); 1.34-1.39 (m, 2H); 1.40-1.57 (m,6H); 2.57 (t, 2H, J=7.4 Hz); 3.17 (d, 2H, J=5.2 Hz); 3.82 (s, 4H); 4.36(t, 1H, J=5.2 Hz); 7.13-7.19 (m, 3H); 7.24-7.29 (m, 2H).

d) 4-hydroxymethyl-4-(4-phenylbutyl)cyclohexanone

A solution of the title compound from the previous step (9.40 g, 30.9mmol) in acetone (150 mL) was mixed with 1 N hydrochloric acid (32 mL)and stirred overnight at room temperature. The reaction solution wasadjusted to pH 8 with 1N sodium hydroxide solution and concentrated tolow volume in a vacuum. The residue was mixed with water (50 mL) andthen extracted with dichloromethane (3×50 mL). The combined organicphases were washed with saturated sodium chloride solution (30 mL),dried with sodium sulphate and concentrated to low volume in a vacuum.Since the product was obtained in pure state, it could be directlyconverted further.

Yield: 7.96 g (99%), light yellow oil

1H-NMR (DMSO-d6): 1.19-1.67 (m, 10H); 2.22 (t, 4H, J=6.8 Hz); 2.59 (t,2H, J=7.5 Hz); 3.30 (d, 2H, J=5.2 Hz); 4.54 (t, 1H, J=5.1 Hz); 7.13-7.21(m, 3H); 7.24-7.29 (m, 2H).

e) 4-(1-ethoxy-ethoxymethyl)-4-(4-phenylbutyl)cyclohexanone

A solution of the title compound of the previous step (7.95 g, 30.5mmol) in absolute dichloromethane (100 mL) was mixed with pyridiniumtosylate (100 mg) and ethyl vinyl ether (2.64 g, 3.51 mL, 36.6 mmol) andstirred overnight at room temperature. The reaction solution was thenwashed with 5% sodium hydrogencarbonate solution, water (2×50 mL each)and saturated sodium chloride solution (50 mL) one after the other,dried with sodium sulphate and concentrated to low volume in a vacuum.The raw product (8.87 g) was purified by means of flash chromatography(400 g, 20×7.5 cm) with cyclohexane/ethyl acetate (9:1).

Yield: 6.97 g (69%), colourless oil

1H-NMR (DMSO-d6): 1.09 (t, 3H, J=7.0 Hz); 1.17 (d, 3H, J=5.3 Hz);1.21-1.32 (m, 2H); 1.43-1.50 (m, 2H); 1.52-1.70 (m, 6H); 2.20-2.26 (m,4H); 2.59 (t, 2H, J=7.5 Hz); 3.24 (d, 1H, J=9.4 Hz); 3.34-3.42 (m, 2H);3.49-3.59 (m, 1H); 4.62 (q, 1H, J=5.3 Hz); 7.14-7.29 (m, 5H).

f) 1-dimethylamino-4-(1-ethoxyethoxymethyl)-4-(4-phenylbutyl)cyclohexanecarbonitrile

Firstly 40% dimethylamine solution (3.74 mL, 24.2 mmol) and then thetitle compound of the previous step (2.04 g, 6.1 mmol) and potassiumcyanide (953 mg, 14.6 mmol) were added to an ice-cooled mixture of 4Nhydrochloric acid (1.52 mL, 6.1 mmol) and methanol (1.7 mL). Thesuspension formed was stirred for 4 h at room temperature. Thesuspension was mixed with water (100 mL) and then extracted with diethylether (3×100 mL). The combined organic phases were dried with sodiumsulphate and concentrated to low volume in a vacuum.

Yield: 2.30 g (97%), light yellow oil

1H-NMR (DMSO-d6): 1.08 (dt, 3H, J=2.5, 7.0 Hz, 1.075 (t, 1.5H, J=7.0Hz); 1.085 (t, 1.5H, J=7.0 Hz); 1.14-1.18 (m, 3H); 1.19-1.39 (m, 6H);1.41-1.68 (m, 6H); 1.89-2.00 (m, 2H); 2.22 (s, 2.6H); 2.23 (s, 3.4H);2.53-2.62 (m, 2H); 3.10 (d, 0.5H, J=9.3 Hz); 3.13 (d, 0.5H, J=9.2 Hz);3.22-3.29 (m, 1H); 3.33-3.39 (m, 1H); 3.47-3.59 (m, 1H); 4.56-4.63 (m,1H); 7.13-7.29 (m, 5H).

g)[4-(1-ethoxyethoxymethyl)-1-phenyl-4-(4-phenylbutyl)cyclohexyl]dimethylamine

A solution of the title compound of the previous step (diastereoisomermixture, 2.30 g, 5.9 mmol) in absolute tetrahydrofuran (30 mL) wasslowly added in drops to an ice-cooled 2M solution of phenylmagnesiumchloride (2.03 g, 7.4 mL, 14.8 mmol) in tetrahydrofuran in argon andthen stirred overnight at room temperature. The reaction solution wasmixed with saturated ammonium chloride solution and water (20 mL each),the phases separated and the aqueous phase extracted with diethyl ether(3×30 mL). The combined organic phases were washed with saturated sodiumchloride solution (30 mL), dried with sodium sulphate and concentratedto low volume in a vacuum. 2.73 g of raw product were formed asdiastereoisomer mixture, which was completely separated by means of MPLC(LiChroprep Si60 15-25 μm, 230 g, 3.6×46 cm) with ethyl acetate/methanol(9:1).

Non-Polar Diastereoisomer:

Yield: 918 mg (35%), light yellow oil

1H-NMR (DMSO-d6): 1.00 (t, 3H, J=7.1 Hz); 1.06 (d, 3H, J=5.3 Hz);1.10-1.20 (m, 2H); 1.21-1.29 (m, 2H); 1.32-1.48 (m, 2H); 1.51-1.62 (m,2H); 1.90 (s, 6H); 1.92-1.99 (m, 4H); 2.59 (t, 2H, J=7.6 Hz); 2.98 (d,1H, J=9.3 Hz); 3.11 (d, 1H, J=9.3 Hz); 3.21-3.29 (m, 2H); 3.39-3.50 (m,2H); 4.48 (q, 1H, J=5.3 Hz); 7.13-7.37 (m, 10H).

h) (−4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol(non-polar diastereoisomer)

A solution of the title compound (non-polar diastereoisomer) of theprevious step (469 mg, 1.1 mmol) in acetone (50 mL) was mixed with 2Nhydrochloric acid (2 mL) and stirred for 18 h at room temperature. Thereaction solution was adjusted to pH 8 with 1N sodium hydroxidesolution, concentrated to low volume in a vacuum, the residue taken upin water (50 mL) and extracted with dichloromethane (3×30 mL). Thecombined organic phases were washed with saturated sodium chloridesolution (30 mL), dried with sodium sulphate and concentrated to lowvolume in a vacuum. The raw product (381 mg) was purified by means offlash chromatography (18 g, 20×2.0 cm) with ethyl acetate/methanol(4:1).

Yield: 325 mg (81%), white solid

Melting point: 105-106° C.

1H-NMR (DMSO-d6): 1.00-1.14 (m, 2H); 1.18-1.28 (m, 2H); 1.29-1.41 (m,4H); 1.49-1.60 (m, 2H); 1.81-1.85 (m, 1H); 1.90 (s, 6H); 1.94-2.06 (m,3H); 2.59 (t, 2H, J=7.7 Hz); 3.02 (d, 2H, J=5.2 Hz); 4.21 (t, 1H, J=5.2Hz); 7.13-7.37 (m, 10H).

13C-NMR (DMSO-d6): 22.4; 28.1; 28.2; 32.2; 34.1; 34.3; 35.9; 36.7; 37.9;60.1; 66.2; 125.5; 125.7; 126.0; 127.2; 127.3; 128.1; 128.2; 137.4;142.4.

LC-MS (Method: ASCA-7MIN-80 degrees.M): m/z: [M+1]+=366.6, Rt 2.38 min.

Example 21(−4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol (polardiastereoisomer) a)[4-(1-ethoxyethoxymethyl)-1-phenyl-4-(4-phenylbutyl)cyclohexyl]dimethylamine

In the synthesis step of Example 20, step g), the polar diastereoisomerwas also obtained in pure state during the chromatographic separation.

Polar diastereoisomer: 700 mg (27%), light yellow oil

1H-NMR (DMSO-d6): 0.96-1.23 (m, 14H); 1.36-1.57 (m, 4H); 1.90 (s, 6H);1.92-2.00 (m, 4H); 2.45-2.47 (m, 1H); 3.16-3.21 (m, 1H); 3.35-3.43 (m,1H); 3.51-3.61 (m, 1H); 4.61 (q, 1H, J=5.2 Hz); 7.09-7.38 (m, 10H).

b) (−4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol(polar diastereoisomer)

A solution of the title compound of the previous step (622 mg, 1.42mmol) in tetrahydrofuran (5 mL) was mixed with glacial acetic acid (3.0mL) and water (1.5 mL) and firstly stirred with reflux for 8 h. Sincethe reaction was not yet complete, the mixture was stirred overnight at50° C. and then once again for 8 h with reflux. Although the conversionwas still not quite complete, the reaction solution was concentrated tolow volume in a vacuum and the residue taken up multiple times in toluol(3×10 mL) and each time concentrated again to low volume in a vacuum.The residue was taken up in 5% sodium hydrogencarbonate solution (30 mL)and extracted with ethyl acetate (3×20 mL). The combined organic phaseswere washed with saturated sodium chloride solution (30 mL), dried withsodium sulphate and concentrated to low volume in a vacuum. Since theraw product still contained starting substance, this was separated bymeans of flash chromatography (400 g, 20×7.5 cm) with ethylacetate/methanol (4:1) (77 mg). Only 245 mg of the very polar targetcompound were obtained at first. Further product (220 mg) was isolatedby washing the column with methanol (500 mL).

Yield: 465 mg (86%), white solid

Melting point: 123° C.

1H-NMR (DMSO-d6): 0.90-1.03 (m, 2H); 1.11 (br s, 4H); 1.35-1.53 (m, 4H);1.92 (br s, 10H); 2.47 (d, 2H, J=8.2 Hz); 3.25 (d, 2H, J=4.9 Hz); 4.35(t, 1H, J=4.7 Hz); 7.09-7.15 (m, 3H); 7.18-7.24 (m, 3H); 7.28-7.39 (m,4H).

13C-NMR (DMSO-d6): 22.3; 28.1; 28.2; 35.2; 35.7; 37.6; 38.9; 59.9; 65.3;125.4; 126.1; 127.4; 128.0; 128.1; 142.3.

Example 22[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamineStep 1 4-benzyl-1-(dimethylamino)-4-((dimethylamino)methyl)cyclohexanecarbonitrile

40% aqueous dimethylamine solution (2.8 mL, 22.1 mmol),4-benzyl-4-((dimethylamino)methyl)cyclohexanone (1.13 g, 4.60 mmol) andpotassium cyanide (0.70 g, 11.0 mmol) were added to a mixture of 4Nhydrochloric acid (3 mL) and methanol (1.05 mL) with ice cooling. Themixture was stirred for 2 d at room temperature and then after addingwater (200 mL) was extracted with ether (4×150 mL). After the solutionwas concentrated, the residue was taken up in dichloromethane (200 mL)and dried overnight with magnesium sulphate, filtered and the solventwas removed in a vacuum. The nitrile was obtained as an oil which wascrystallised through.

Yield: 1.06 g (77%)

¹H-NMR (DMSO-d₆): 1.23 (2H, m); 1.74 (2H, m); 2.16 (6H, s); 2.24 (6H,s); 2.32 (2H, m); 2.68 (2H, s); 7.16 (5H, m).

Step 2[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamine

The title compound of step 1 (0.88 g, 2.94 mmol) was dissolved in THF(35 mL) and mixed in drops with 2M phenylmagnesium chloride solution(5.1 mL, 10.2 mmol) with ice cooling. The reaction solution was heatedto boiling for 8 h. For work up the solution was mixed with 20% NH₄Clsolution (0.6 mL) and water (0.4 mL) with ice cooling, extracted withether (3×25 mL), the ether solution was washed with water, dried(Na₂SO₄) and concentrated to low volume in a vacuum. The residue waspurified by column chromatography with EtOH/EE (1:20). 2 fractions wereobtained, wherein according to LCMS, inter alia, the more polar fraction(300 mg) contained the desired substance.

Yield: 90 mg (9%)

¹H-NMR (DMSO-d₆): 1.23 (4H, m); 1.39 (2H, m); 1.82 (2H, s); 1.89 (6H,s); 2.09 (6H, s); 2.10 (2H, m); 2.73 (2H, s); 7.25 (10H, m).

Example 23(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethylamine Step 15-cyano-2-oxo-5-phenyl-cyclohexane carboxylic acid ethyl ester

NaNH₂ (100 g, 2560 mmol) was added in portions to a solution of benzylcyanide (35.6 g, 304 mmol) and bromopropionic acid ethyl ester (126 g,694 mmol) in dry toluol (1070 mL) with stirring over 3 h at 0 to 5° C.The mixture was then heated to boiling for 6 h (the reaction was firstlyexothermic and therefore the heating bath had to be removedintermittently). The mixture was then cooled to 0° C. and quenched witha mixture of acetic acid (240 mL) and water (120 mL). The toluol phasewas separated, the aqueous phase extracted with toluol (2×200 mL) andthe combined organic phase washed with NaHCO₃ solution (2×200 mL) andwater (2×200 mL) and dried with Na₂SO₄. The solvent was then removed ina vacuum.

Yield: 70.8 mg (86%), brown solid

¹H-NMR (DMSO-d₆): 1.25 (3H, t); 2.24-2.88 (6H, m); 4.19 (2H, q); 7.50(5H, m).

Step 2 4-oxo-1-phenyl-cyclohexane carbonitrile

The title compound of step 1 (70.8 g, 261 mmol) in a mixture of aceticacid (810 mL) and concentrated hydrochloric acid (354 mL) was heated toboiling for 3.5 h under DC control. The mixture was then cooled to 0 to5° C., diluted with water (1 L), saturated with NaCl and extracted coldwith ethyl acetate (3×300 mL). The ethyl acetate phase was washed withwater and concentrated to low volume in a vacuum. The solid residue wasdissolved once again in ethyl acetate, washed with NaHCO₃ solution andconcentrated until dry.

Yield 43.3 g (83%), yellow solid The residue was used for the conversionwith ethylene glycol without further purification

¹H-NMR (DMSO-d₆): 2.41 (6H, m); 2.71 (2H, m); 7.40 (3H, m); 7.60 (2H,m).

¹³C-NMR (DMSO-d₆): 35.3; 38.1; 42.3; 121.7; 125.6; 128.2; 129.0; 139.2;206.7.

Step 3 8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile

The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol(27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition ofp-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 hwith reflux. After the reaction had ended, the mixture was cooled,washed with NaHCO₃ solution and saturated NaCl solution, dried withNa₂SO₄ and concentrated to low volume in a vacuum.

Yield: 48.8 g (96%), solid

¹H-NMR (DMSO-d₆): 1.85 (4H, m); 2.13 (4H, m); 3.92 (4H, s); 7.44 (5H,m).

¹³C-NMR (DMSO-d₆): 32.1; 34.0; 42.5; 63.8; 106.1; 122.1; 125.5; 128.0;128.9; 139.9.

Step 4 C-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-methylamine

A solution of the title compound of step 3 (10.0 g, 41.1 mmol) in dryTHF (70 mL) was slowly added to a mixture of LiAlH₄ (1.87 g, 49.3 mmol)in dry THF (25 mL) in a protective gas. The mixture was then stirred for3 h with reflux. After the reaction mixture had cooled, a solution ofwater (1.87 mL, 104 mmol) diluted with a little THF was added in dropswith ice cooling and subsequently stirred for 10 min. 15% aqueous NaOH(1.87 mL, 8.17 mmol) diluted with a little THF was then added in dropsand water (5.6 mL) was then added again. The precipitate formed wasfiltered over diatomaceous earth and the solvent removed in a vacuum.The amine remained as residue.

Yield: 7.96 g, (78%), yellow oil

¹³C-NMR (DMSO-d₆): 29.9; 31.0; 42.7; 53.9; 63.5; 108.3; 125.5; 126.8;128.2; 143.8.

Step 5 Dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-amine

The title compound of step 4 (5.40 g, 21.8 mmol) was dissolved inacetonitrile (150 mL), and a cloudy solution was formed. Aqueous 37%formalin solution (30.6 mL, 407 mmol) was added. The batch was stirredfor 20 min at RT and then mixed with sodium cyanoboron hydride (5.76 g,91.7 mmol). The reaction was followed by DC in chloroform/methanol(9:1). After 4 h the solution was adjusted to pH 7 with acetic acid andconcentrated to low volume in a vacuum. The residue was taken up inchloroform, washed with NaHCO₃ solution and the aqueous phase extractedwith ether. The combined organic phases were dried over Na₂SO₄ andconcentrated to low volume in a vacuum. The raw product was purified byflash chromatography with chloroform/methanol (50:1→20:1→9:1).

Yield: 5.40 g (67%)

¹H-NMR (DMSO-d₆): 1.32 (2H, m); 1.56 (2H, m); 1.77 (2H, m); 1.91 (6H,s); 2.14 (2H, m); 2.28 (2H, s); 3.80 (4H, m); 7.16-7.39 (5H, m).

Step 6 4-dimethylaminomethyl-4-phenyl-cyclohexanone

The title compound of step 5 (5.40 g, 19.6 mmol) was dissolved in 5%H₂SO₄ (300 mL) and stirred for 1 d at RT. The solution was then washedwith ether three times and the ether phase discarded. The aqueous phasewas made alkaline with 5N NaOH with ice cooling and extracted withdichloromethane three times. The organic phase was washed with a littlewater, dried over Na₂SO₄ and concentrated to low volume in a vacuum.

Yield: 4.89 g (100%)

¹H-NMR (DMSO-d₆): 1.92 (6H, s); 1.94-2.00 (2H, m); 2.07-2.25 (4H, m);2.39-2.46 (4H, m); 7.23 (1H, m); 7.37 (2H, m); 7.48 (2H, m).

Step 7 1-dimethylamino-4-dimethylaminomethyl-4-phenyl-cyclohexanecarbonitrile

40% aqueous dimethylamine solution (12.8 mL, 21.1 mmol) was added indrops to a mixture of 4N hydrochloric acid (5 mL) and methanol (3 mL)with ice cooling. The title compound of step 6 (4.89 g, 21.1 mmol) andKCN (3.30 g, 50.7 mmol) were then added one after the other. The mixturewas stirred for 3 d at RT. For work up the batch was mixed with water(10 mL) and extracted with diethyl ether (3×20 mL). The ether phase wasconcentrated to low volume in a vacuum, the residue was taken up inCH₂Cl₂, dried over Na₂SO₄ and concentrated to low volume in a vacuum.

Yield: 5.16 g (86%)

¹H-NMR (DMSO-d₆): 1.28 (2H, m); 1.69 (2H, m); 1.94 (6H, s); 2.05 (2H,m); 2.15 (6H, s); 2.26 (2H, m); 2.37 (2H, s); 7.19 (1H, m); 7.35 (4H,m).

Step 8 (4-dimethylaminomethyl-1,4-diphenyl-cyclohexyl)-dimethylamine

2M phenylmagnesium chloride solution in THF (3.5 mL, 7.0 mmol) wasslowly added in drops to a solution of the title compound of step 7(1.00 g, 3.5 mmol) in abs. THF (10 mL) in a nitrogen atmosphere and withice cooling at 10° C. The solution was stirred for 20 h at RT. Then 20%NH₄Cl solution (5 mL) and water (2 mL) were added and the solution wasextracted with ether (3×5 mL). The combined organic phases were washedwith water (2 mL) and saturated NaCl solution (2 mL), dried over Na₂SO₄and concentrated to low volume in a vacuum. By flash chromatography ofthe residue with chloroform/methanol (20:1) a salt of the product wasobtained that was released with 1N NaOH, extracted with chloroform,dried over Na₂SO₄, and the solvent removed from it in a vacuum.

Yield: 336 mg (28%) non-polar diastereoisomer, porous solid

¹H-NMR (CDCl₃): 1.39 (2H, m); 1.65-1.78 (2H, m); 1.82 (6H, s); 1.96 (6H,s); 2.20 (2H, s); 2.28-2.41 (4H, m); 7.15-7.44 (10H, m).

Example 24(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide(non-polar diastereomer)

The title compound from Example 8 (202 mg, 0.656 mmol) was provided indry THF (20 mL) and mixed with TEA (97 μL, 0.702 mmol). Cinnamic acidchloride (116 mg, 0.702 mmol) was then added. The batch was stirred for20 h at room temperature. After this reaction time the batch wasconcentrated until dry in a vacuum. The residue was taken up in ethylacetate (20 mL) and washed with saturated NaHCO₃ solution (2×20 mL) andsaturated NaCl solution (2×20 mL). The organic phase was dried overNa₂SO₄ and concentrated to low volume in a vacuum. The residue waspurified by flash chromatography with chloroform/methanol (20:1).

Yield: 95 mg (33%)

¹H-NMR (DMSO-d₆): 1.61 (2H, bs); 1.97 (5H, bs); 2.45 (1H, m); 2.49 (4H,m); 2.94 (3H, bs); 3.23 (1H, s); 3.35 (1H, s); 3.35 (2H, m); 7.02 (1H,m); 7.25 (2H, m); 7.34 (9H, m); 7.46 (2H, m); 7.57 (2H, m).

Example 33(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine(polar diastereomer) Step 14-benzyl-4-dimethylaminomethyl-1-methylamino-cyclohexane carbonitrile

40% aqueous methylamine solution (15.3 mL, 121 mmol) and4-benzyl-4-((dimethylamino)methyl)cyclohexanone (6.20 g, 25.3 mmol)dissolved in methanol (25 mL) were added to a solution of 4Nhydrochloric acid (6.6 mL) and methanol (4.00 mL) cooled to 0° C. Thereaction mixture was then mixed with potassium cyanide (4.00 g, 60 mmol)and stirred for 5 d at room temperature. For work up the mixture wasdiluted with water (180 mL) and extracted with ether (3×100 mL). Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated until dry in a vacuum.

Yield: 5.80 g (81%)

¹H-NMR (DMSO-d₆): 1.35 (5H, m); 1.58 (8H, m); 2.25 (6H, m); 2.65 (4H,m); 4.35 (1H, m); 7.14 (3H, m); 7.28 (2H, m).

Step 2(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine(polar diastereomer)

Phenyl lithium (33 mL, 60 mmol, 1.8 M solution in dibutyl ether) wasmixed in drops with a solution of the title compound from step 1 (5.70g, 20 mmol) in diethyl ether (60 mL) in argon and at room temperature.During this, the temperature of the reaction solution rose to 35° C. anda solid separated out. The reaction mixture was stirred with reflux for30 min, then hydrolysed in an ice bath with 20% NH₄Cl solution (40 mL)and the organic phase was separated. The aqueous phase was extractedwith ether (3×100 mL). The combined organic phases were dried overNa₂SO₄, filtered and concentrated to low volume in a vacuum. The residuewas purified by flash chromatography with chloroform/methanol(20:1→9:1→1:1→1% TEA). The polar diastereomer was obtained in cleanform. The non-polar diastereomer was isolated in impure state.

Yield: 1.40 g (21%), polar diastereomer

¹H-NMR (DMSO-d₆): 1.13 (2H, m); 1.74 (4H, m); 1.89 (3H, m); 1.96 (4H,m); 2.23 (6H, s); 2.68 (2H, s); 7.15 (4H, m); 7.26 (2H, m); 7.33 (2H,m); 7.48 (2H, m).

Example 34(1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethylamine(polar diastereomer)

A solution of the title compound from Example 33 (1.40 g, 4.16 mmol) andformalin (5.8 mL, 37% aqueous solution) in acetonitrile (40 mL) wasmixed in portions with sodium cyanoboron hydride (1.03 g, 16.6 mmol) andstirred for 45 min at room temperature. Concentrated acetic acid wasthen added until a neutral reaction occurred and the mixture stirred for45 min at room temperature. For work up the solvent was removed in avacuum, the residue taken up in 2N NaOH (40 mL) and then extracted withether (3×40 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated to low volume in a vacuum. The remaining residue waspurified by flash chromatography with ethyl acetate(methanol→methanol+2% TEA).

Yield: 200 mg (14%)

¹H-NMR (DMSO-d₆): 1.10 (2H, m); 1.56 (2H, m); 1.89 (6H, s); 2.00 (2H,m); 2.04 (2H, s); 2.11 (2H, m); 2.25 (6H, s); 2.58 (2H, m); 7.19 (10H,m).

Example 37[4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethylamine (polardiastereomer)

2M phenylmagnesium chloride solution in THF (3.5 mL, 7.0 mmol) wasslowly added in drops to a solution of the title compound of Example 23,step 7 (1.00 g, 3.5 mmol) in abs. THF (10 mL) in a nitrogen atmosphereand with ice cooling at 0-10° C. The solution was stirred for 20 h atRT. 20% NH₄Cl solution (5 mL) and water (2 mL) were then added and thesolution extracted with ether (3×5 mL). The combined organic phases werewashed with water (2 mL) and saturated NaCl solution (2 mL), dried overNa₂SO₄, filtered and concentrated to low volume in a vacuum. Flashchromatography with chloroform/methanol (20:1→9:1→4:1→1:1→1:1+1%NH₃→MeOH+1% NH₃) gave the hydrochloride of the non-polar diastereoisomerat 20:1, and this was released with 1N NaOH, extracted with chloroform,dried over Na₂SO₄ and concentrated to low volume in a vacuum. The polardiastereoisomer was obtained with MeOH+1% NH₃. Since the first spectrumalso indicated a salt here, the polar diastereoisomer was also releasedwith 1N NaOH, extracted with chloroform, dried over Na₂SO₄ andconcentrated to low volume in a vacuum.

Yield: 81 mg (7%), polar diastereoisomer, porous solid

¹H-NMR (DMSO-d₆): 1.59 (2H, breit); 1.77-1.86 (2H, m); 1.89 (6H, s);1.95 (6H, s); 1.97-2.05 (2H, m); 2.25 (2H, m); 2.39 (2H, s); 7.07-7.37(10H, m).

Example 42(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide(polar diastereomer) Step 14-dimethylamino-4-(3-fluorophenyl)-cyclohexane carbaldehyde

KOtBu (2.15 g, 19.2 mmol) dissolved in abs. THF (25 mL) was added indrops to a solution of (methoxymethyl)triphenylphosphonium chloride(6.58 g, 19.2 mmol) in abs. THF (25 mL) at 0° C. in argon. The resultingred solution was mixed after 30 min at 0° C. with a solution of4-dimethylamino-4-(3-fluorophenyl)cyclohexanone (3.0 g, 12.76 mmol) inabs. THF (25 mL) and stirred overnight at RT. The solvent was removed ina vacuum, the residue mixed with 1M sulphuric acid (50 mL) and stirredfor 2 h. The precipitate precipitated out during this was separated andthe filtrate (pH 1) washed with ether (6×30 mL). The aqueous solutionwas adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate(3×50 mL). The combined organic phases were dried over Na₂SO₄ andconcentrated to low volume in a vacuum.

Yield: 3.20 g (100%), brown oil

Diastereomer mixture 1:1

¹H-NMR (DMSO-d₆): 1.20 (1H, m); 1.62 (2H, m); 1.75 (3H, m); 1.93 (6H,s); 2.37 (3H, m); 7.12 (3H, m); 7.40 (1H, m); 9.50 (0.5H, s); 9.62(0.5H, s).

Step 2 4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexanecarbaldehyde

A solution of the title compound of step 1 (2.73 g, 10.95 mmol) in abs.dichloromethane (50 mL) was mixed with tert-BuOK (1.47 g, 13.14 mmol)and methyl iodide (747 μl, 12 mmol) at 0° C. in argon. After 30 min thebatch was heated to RT and then stirred overnight (solid separated out).The reaction mixture was mixed with saturated NaCl solution (50 mL) andextracted with dichloromethane (3×30 mL). The combined organic phaseswere dried over Na₂SO₄, concentrated to low volume in a vacuum and theremaining residue was purified by flash chromatography with ethylacetate/MeOH 20:1.

Yield: 1.39 g (51%)

¹H-NMR (DMSO-d₆): 0.85 (1.5H, s); 1.00 (1.5H, s); 1.50 (1H, m);1.54-1.77 (4H, m); 1.89-1.95 (7H, m); 2.11-2.31 (2H, m); 7.11 (3H, m);7.38 (1H, m); 9.36 (0.5H, s); 9.44 (0.5H, s).

Step 3 4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexanecarbaldehyde oxime

A solution of the title compound of step 2 (1.38 g, 5.53 mmol) andhydroxylamine hydrochloride (576 mg, 8.3 mmol) in abs. ethanol (20 mL)were mixed with Amberlyst A 21 (3.9 g) and stirred for 16 h at RT. Theion exchanger was filtered off, the solution concentrated to low volumeand the residue made alkaline with 1N NaOH. The aqueous phase wasextracted with ethyl acetate, dried over Na₂SO₄ and concentrated to lowvolume in a vacuum.

Yield: 1.54 g (100%)

Step 4[4-aminomethyl-1-(3-fluorophenyl)-4-methyl-cyclohexyl]-dimethylamine

Lithium aluminium hydride (440 mg, 11.6 mmol) was suspended in abs. THF(50 mL) in argon, mixed in drops with a solution of the title compoundof step 3 (1.54 g, 5.53 mmol) in abs. THF (20 mL) and boiled for 4 hwith reflux. The batch was then hydrolysed with water (10 mL) at 10° C.and filtered off over diatomaceous earth. The THF was removed in avacuum, the residue adjusted to pH 11 with 1N NaOH and extracted withethyl acetate. The combined organic phases were dried over Na₂SO₄,concentrated to low volume in a vacuum and the remaining residue waspurified by flash chromatography with MeOH+2% NH₃.

Yield: 435 mg (30%, non-polar diastereomer)

¹H-NMR (DMSO-d₆): 0.85 (3H, s); 1.03 (2H, m); 1.29 (2H, m); 1.83 (2H,m); 1.91 (6H, s); 2.08 (2H, m); 2.17 (2H, s); 7.09 (3H, m); 7.38 (1H,m).

Yield: 510 mg (35%, polar diastereomer)

¹H-NMR (DMSO-d₆): 0.72 (3H, s); 1.00 (2H, m); 1.49 (2H, m); 1.78 (2H,m); 1.91 (6H, s); 2.07 (2H, m); 2.38 (2H, s); 7.09 (3H, m); 7.39 (1H,m).

Step 5(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide(polar diastereomer)

A solution of the title compound of step 4 (polar diastereomer) (250 mg,0.94 mmol) and Hünig's base (169 μl, 1.0 mmol) in abs. dichloromethane(10 mL) was mixed with cinnamic acid chloride (166 mg 1.0 mmol) andstirred for 24 h at RT. The organic solution was washed with saturatedNaHCO₃ solution and saturated NaCl solution, dried over Na₂SO₄,concentrated to low volume in a vacuum and the remaining residue waspurified by flash chromatography with ethyl acetate/MeOH 4:1.

Yield: 295 mg (80%), porous solid

¹H-NMR (DMSO-d₆): 0.77 (3H, s); 1.03 (2H, m); 1.53 (2H, m); 1.87 (2H,m); 1.93 (6H, s); 2.12 (2H, m); 3.17 (2H, d); 6.76 (1H, d); 7.07 (3H,m); 7.37 (5H, m); 7.56 (2H, m); 7.96 (1H, t).

Example 48[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer) Step 1N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-butyramide

The title compound from Example 8 (308 mg, 1.0 mmol) was provided inabs. THF (15 mL) and mixed with TEA (165 μL, 1.2 mmol) and butyrylchloride (103 mg, 1.2 mmol, V=124 μL). The batch was stirred for 20 h atroom temperature and then concentrated until dry in a vacuum. Theresidue was taken up in ethyl acetate (20 mL) and washed with saturatedNaHCO₃ solution (2×20 mL) and saturated NaCl solution (2×20 mL). Theorganic phase was dried over Na₂SO₄ and concentrated to low volume in avacuum. The residue was purified by flash chromatography withchloroform/methanol (50:1).

Yield: 206 mg (53%)

¹H-NMR (DMSO-d₆): 0.76 (3H, t); 1.41 (2H, q); 1.60 (2H, m); 1.95 (6H,s); 2.22 (4H, 2.33 (2H, m); 2.82 (3H, s); 7.20-7.39 (10H, m).

Step 2 [4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

The title compound from step 1 (200 mg, 0.528 mmol) was dissolved inabs. THF (15 mL). LiAlH₄ (39 mg, 1.06 mmol) was added in argon. Thebatch was boiled for 7 h with reflux. The batch was then cooled to roomtemperature, mixed with THF (12 mL) and H₂O (5 mL) with ice cooling andsubsequently stirred for 30 min. The batch was filtered over a frittedglass filter with diatomaceous earth and subsequently rinsed withdichloromethane (50 mL). The combined filtrates were concentrated to lowvolume in a vacuum.

Yield: 194 mg (100%), oil

¹H-NMR (DMSO-d₆): 0.74 (3H, t); 1.12 (4H, m); 1.73 (4H, wide); 1.83 (6H,s); 1.90 (3H, s); 1.92 (1H, s); 1.96 (2H, wide); 2.25 (4H, wide); 7.25(2H, m); 7.38 (8H, m).

Example 49[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (polardiastereomer)

The title compound from Example 9 (308 mg, 1.0 mmol) and butyricaldehyde (72 mg, 1.0 mmol, V=89 μL) were provided in abs. acetonitrile(30 mL) and mixed with sodium cyanoboron hydride (250 mg, 4.0 mmol). Thebatch was stirred for 45 min at room temperature, then mixed with conc.acetic acid (approx. 500 μL) and stirred a further 45 min at roomtemperature. For work up the batch was concentrated until dry in avacuum. The residue was mixed with 2N NaOH and extracted with ether(3×20 mL). The combined organic phases were dried over Na₂SO₄ andconcentrated to low volume in a vacuum. The residue was purified byflash chromatography with chloroform/methanol (9:1).

Yield: 111 mg (30%), oil

¹H-NMR (DMSO-d₆): 0.86 (3H, t); 1.30 (6H, m); 2.05 (12H, m); 2.35 (5H,m); 7.29 (10H, m).

Example 50[40-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer) Step 1N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-benzamide

The title compound from Example 8 (308 mg, 1.0 mmol) was provided inabs. THF (15 mL) and mixed with TEA (165 μL, 1.2 mmol) and benzoylchloride (168 mg, 1.2 mmol, V=147 μL). The batch was stirred for 16 h atroom temperature and then concentrated until dry in a vacuum. Theresidue was taken up in ethyl acetate (20 mL), washed with saturatedNaHCO₃ solution (2×20 mL) and saturated NaCl solution (2×20 mL). Theorganic phase was dried over Na₂SO₄ and concentrated to low volume in avacuum. The residue was purified by flash chromatography withchloroform/methanol (20:1).

Yield: 169 mg (41%)

¹H-NMR (DMSO-d₆): 1.75 (2H, m); 1.98 (6H, s); 2.38 (3H, m); 2.55 (2H,m); 2.69 (4H, s); 7.24-7.41 (13H, m); 7.54 (2H, d).

Step 2 [4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

The title compound from step 1 (160 mg, 0.387 mmol) was dissolved inabs. THF (15 mL) and mixed with LiAlH₄ (29 mg, 0.775 mmol) in argon. Thebatch was boiled for 7 h with reflux and then cooled to roomtemperature. THF (5 mL) and H₂O (5 mL) were added to the batch with icecooling and subsequently stirred for 30 min. The batch was filtered overa fitted glass filter with diatomaceous earth and subsequently rinsedwith dichloromethane (50 mL). The combined filtrates were concentratedto low volume in vacuum.

Yield: 149 mg (97%)

¹H-NMR (DMSO-d₆): 1.78 (3H, s); 1.85 (10H, s); 2.33 (4H, m); 3.14 (2H,bs); 7.04-7.20 (4H, m); 7.31 (2H, m); 7.40 (9H, m).

Example 51[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (polardiastereomer) Step 1N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-benzamide

The title compound from Example 9 (308 mg, 1.0 mmol) was provided inabs. THF (15 mL) and mixed with TEA (165 μL, 1.2 mmol) and benzoylchloride (168 mg, 1.2 mmol, V=147 μL). The batch was stirred for 16 h atroom temperature and then concentrated until dry in a vacuum. Theresidue was taken up in ethyl acetate (20 mL), washed with saturatedNaHCO₃ solution (2×20 mL) and saturated NaCl solution (2×20 mL). Theorganic phase was dried over Na₂SO₄ and concentrated to low volume in avacuum. The residue was purified by flash chromatography withchloroform/methanol (20:1).

Yield: 304 mg (74%)

¹H-NMR (DMSO-d₆): 1.63 (2H, m); 1.92-2.00 (10H, m); 2.52 (1H, m); 2.76(3H, s); 7.16 (1H, m); 7.28 (4H, m); 7.39-7.49 (10H, m).

Step 2 [4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer)

The title compound from step 1 (290 mg, 0.702 mmol) was dissolved inabs. THF (15 mL) and mixed with LiAlH₄ (52 mg, 1.40 mmol) in argon. Thebatch was boiled for 7 h with reflux and then cooled to roomtemperature. The batch was filtered over a fritted glass filter withdiatomaceous earth and subsequently rinsed with dichloromethane (50 mL).The combined filtrates were concentrated to low volume in vacuum.

Yield: 250 mg (89%)

¹H-NMR (DMSO-d₆): 1.43 (1H, m); 1.72-1.76 (1H, m); 1.89 (3H, s); 1.99(6H, s); 2.42 (3 H, wide); 3.25 (2H, bs); 7.16-7.39 (15H, m).

Example 662-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]acetic acid(polar diastereomer) Step 1[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]acetic acidtert-butyl ester

A solution of the title compound from Example 9 (246 mg, 0.8 mmol) andbromoacetic acid tert-butyl ester (132 μl, 0.9 mmol) in abs. DMF (10 mL)was mixed with potassium carbonate (124 mg, 0.9 mmol) and stirred for 20h at RT. The solvent was then removed in a vacuum, the residue dissolvedin dichloromethane (20 mL), washed with water (2×10 mL) and saturatedNaCl solution (2×10 mL) and dried over Na₂SO₄. The organic solution wasconcentrated to low volume in a vacuum and the remaining residue waspurified by flash chromatography with chloroform/MeOH 20:1.

Yield: 133 mg (39%)

¹H-NMR (CDCl₃): 1.44 (9H, s); 1.78 (2H, bs); 1.95 (2H, bs); 2.09 (6H,s); 2.21 (3H, s); 2.43 (4H, m); 2.92 (2H, s); 7.16-7.31 (10H, m).

Step 2 2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]aceticacid (polar diastereomer)

The title compound from step 1 (130 mg, 0.3 mmol) was dissolved inanisole (0.5 mL) and trifluoroacetic acid (2.5 mL) and stirred for 20 hat RT. The mixture was then concentrated until dry in a vacuum, 1N NaOHstirred through the solid residue, the solid filtered, washed with waterand dried in a vacuum.

Yield: 69 mg (63%)

Melting point: 270-273° C.

¹H-NMR (DMSO-d₆): 1.70 (3H, br); 1.96 (6H, s); 2.00 (3H, s); 2.25 (2H,m); 2.45 (4H, m); 3.32 (2H, 5); 7.14 (2H, m); 7.25 (8H, m).

The following compound was obtained following a specification such asdescribed in Example 66 except that the educts listed in Table 1-1 wereused.

TABLE 1-1 Cy (%)/MS Ex. No. Educt Product (m/z) 67 Ex. 82-[(4-dimethylamino-1,4-diphenyl- 63 (367)cyclohexyl)-methylamino]acetic acid (non-polar diastereomer)

Example 68[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer) Step 1[8-(4-methoxy-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethylamine

Magnesium (3.65 g, 150 mmol) and an iodine crystal were provided in anitrogen atmosphere and heated. Abs. ether (10 mL) was then added and asolution of 4-bromoanisole (18.8 mL, 150 mmol) in abs. ether (150 mL)was added in drops so that the ether lightly boiled. The solution formedwas subsequently stirred for 1 h at RT and then mixed in drops with asolution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile(10.5 g, 50.0 mmol) in abs. THF (100 mL), and the solution heated to37-40° C. until boiling during the addition. A precipitate separated outand the batch was stirred overnight at RT. The solution was mixed withNH₄Cl solution with ice cooling, the phases were separated, the aqueousphase extracted three times with ether, the combined organic phaseswashed with saturated NaCl solution and water, dried over Na₂SO₄ andconcentrated to low volume in a vacuum. Flash chromatography of theresidue with ethyl acetate/methanol (20:1→9:1→4:1→1:4→MeOH) gave thedesired product.

Yield: 6.80 g (47%)

Step 2 4-dimethylamino-4-(4-methoxy-phenyl)-cyclohexanone

The title compound from step 1 (6.80 g, 23 mmol) was dissolved in ether(100 mL), mixed with 5% H₂SO₄ (100 mL) and the solution vigorouslystirred for 2 d at RT. The phases were separated and the ether phasediscarded. The aqueous phase was made alkaline with 5N NaOH with icecooling and extracted three times with ether, the combined organicphases were then washed with water, dried over Na₂SO₄ and concentratedto low volume in a vacuum.

Yield: 4.20 g (73%)

¹H-NMR (DMSO-d₆): 2.00 (6H, s); 2.01-2.14 (4H, m); 2.42-2.48 (2H, m);2.53-2.63 (2H, m); 3.76 (3H, s); 6.93 (2H, d); 7.34 (2H, d).

Step 3 4-dimethylamino-4-(4-methoxy-phenyl)-1-methylamino-cyclohexanecarbonitrile

40% aqueous methylamine solution (3.50 mL, 40.1 mmol) was added in dropsto a mixture of 4N hydrochloric acid (1.98 mL) and methanol (2.3 mL)with ice cooling. A solution of the title compound from step 2 (2.00 mg,8.09 mmol) in methanol (30 mL) and potassium cyanide (1.32 g, 20.3 mmol)were then added. The mixture was stirred for 3 d at RT and then afteradding water (10 mL) was extracted 4× with ether. The combined organicphases were dried over Na₂SO₄ and concentrated to low volume in avacuum.

Yield: 2.23 g (96%), impure product, was converted further in raw state

¹H-NMR (DMSO-d₆): 1.29 (1H, m); 1.61 (1H, m); 1.69-1.86 (4H, m); 1.90(6H, d); 1.93-2.04 (2H, m); 2.28 (3H, dd); 2.75 (1H, dq); 3.75 (3H, d);6.90 (2H, d); 7.23 (2H, dd).

Step 4[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

Phenyl lithium (12.9 mL, 23.3 mmol, 1.8 M solution in dibutyl ether) wasprovided in argon and mixed in drops with a solution of the titlecompound from step 3 (2.23 g, 7.76 mmol) in abs. diethyl ether (30 mL)at RT. During this, the reaction solution heated to 35° C. and a solidseparated out. The reaction mixture was stirred for 1 h with reflux(bath 50° C.), then hydrolysed in the ice bath (0-10° C.) with 20% NH₄Clsolution (20 mL) and the organic phase was separated. The aqueous phasewas extracted with ether (3×50 mL). The combined organic solutions weredried over Na₂SO₄ and concentrated to low volume in a vacuum. By meansof flash chromatography (100 g silica gel) with ethyl acetate/methanol(20:1→9:1→MeOH→MeOH+2% NH₃) the non-polar diastereoisomer was obtainedin a mixed fraction with starting substance and ketone and lastly thepolar diastereoisomer. The mixed fraction with non-polar diastereoisomerwas purified again by flash chromatography with dichloromethane/methanol(50:1→20:1→9:1→4:1)

Yield: 232 mg (9%), non-polar diastereoisomer

¹H-NMR (CDCl₃): 1.71 (2H, m); 1.98 (4H, m); 1.99 (6H, s); 2.11 (1H, m);2.19-2.41 (5H, m); 3.81 (3H, s); 6.91 (2H, m); 7.27 (3H, m); 7.37 (2H,m); 7.48 (2H, m).

Example 69[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine(polar diastereomer)

The polar diastereomer could also be isolated during the synthesis ofthe title compound from Example 68 as part of step 4.

Yield: 177 mg (7%), polar diastereoisomer

¹H-NMR (CDCl₃): 1.58-1.92 (4H, m); 2.03 (4H, m); 2.07 (6H, s); 2.10-2.18(2H, m); 2.29 (2H, m); 3.80 (3H, s); 6.87 (2H, d); 7.14 (1H, m);7.20-7.33 (6H, m).

The following compounds were obtained following a specification such asdescribed in Examples 68 and 69 except that the bromides orcorresponding Grignard reagents as well as the carbonitriles as listedin Table 1-2 were used.

TABLE 1-2 Cy (%)/ Ex. MS No. R—Br/MgX Carbonitrile Product (m/z)  38

(CN-A) dimethyl-(4-methylamino- 4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine (non- polar diastereomer) 20 (315)  39

(CN-A) dimethyl-(4-methylamino- 4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine (polar diastereomer) 33 (315)  46

(CN-A) (1-butyl-4-methylamino- 4-phenyl-cyclohexyl)- dimethylamine(non-polar diastereomer)  2 (289)  47

(CN-A) (1-butyl-4-methylamino- 4-phenyl-cyclohexyl)- dimethylamine(polar diastereomer) 28 (289)  60

(CN-A) [4-(cyclopentyl-methyl)- 4-dimethylamino-1- phenyl-cyclohexyl]-methylamine (non-polar diastereomer)  8 (315)  61

(CN-A) [4-(cyclopentyl-methyl)- 4-dimethylamino-1- phenyl-cyclohexyl]-methylamine (polar diastereomer) 36 (315)  70

(CN-A) dimethyl-[4-methylamino- 4-phenyl-1-[4-(trifluoromethyl)-phenyl]- cyclohexyl]-amine (non- polar diastereomer) 8 (377)  71

(CN-A) dimethyl-[4-methylamino- 4-phenyl-1-[4-(trifluoromethyl)-phenyl]- cyclohexyl]-amine (polar diastereomer)  7(377) 147

(CN-B) (1,4-diphenyl-4- pyrrolidin-1-yl- cyclohexyl)-methylamine (polardiastereomer)  8 (335) 148

(CN-B) (1,4-diphenyl-4- pyrrolidin-1-yl- cyclohexyl)-methylamine(non-polar diastereomer)  3 (335) Carbonitriles:8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (CN-A)8-(pyrrolidin-1-y1)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (CN-B)

Example 74[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine(polar diastereomer)

A solution of the title compound from Example 69 (111 mg, 0.33 mmol) andformalin (0.45 mL, 37% aqueous solution) in acetonitrile (3 mL) wasmixed with sodium cyanoboron hydride (83 mg, 1.32 mmol) and stirred for45 min at RT. Conc. acetic acid was then added until a neutral reactionoccurred and the mixture stirred for 45 min at RT. For work up thesolvent was removed in a vacuum, the residue taken up with 2N NaCl (5mL) and then extracted with ether (3×10 mL). The organic solution wasdried over Na₂SO₄ and concentrated to low volume in a vacuum. Theremaining residue was purified by means of flash chromatography withethyl acetate/methanol (1:2→MeOH).

Yield: 82 mg (71%)

¹H-NMR (CDCl₃): 1.62-2.05 (4H, m); 2.07 (12H, s); 2.37 (4H, m); 3.79(3H, s); (6.77 (3 H, s); 6.83 (2H, d); 7.20 (3H, m); 7.28 (4H, m).

Example 75[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

A solution of the title compound from Example 68 (96 mg, 0.28 mmol) andformalin (0.39 mL, 37% aqueous solution) in acetonitrile (3 mL) wasmixed with sodium cyanoboron hydride (72 mg, 1.15 mmol) and stirred for45 min at RT. Conc. acetic acid was then added until a neutral reactionoccurred and the mixture stirred for 45 min at RT. For work up thesolvent was removed in a vacuum, the residue taken up in 2N NaCl (5 mL)and then extracted with ether (3×10 mL). The organic solution was driedover Na₂SO₄ and concentrated to low volume in a vacuum. The remainingresidue was purified by means of flash chromatography with ethylacetate/methanol (2:1→1:1→1:1+2% NH₃).

Yield: 62 mg (62%)

¹H-NMR (CDCl₃): 1.59 (4H, m); 1.92 (6H, s); 1.93 (6H, s); 2.48 (4H, m);3.81 (3H, s); 6.90 (2H, m); 7.20-7.41 (7H, m).

The following compounds were obtained following a specification such asdescribed in Examples 74 and 75 except that the educts listed in Table1-3 were used.

TABLE 1-3 Cy Ex. Educt (%)/MS No. (Ex. No.) Product (m/z) 40 39[4-(dimethylamino)-4-phenyl-1-thiophen- 73 (329)2-yl-cyclohexyl]-dimethylamine (polar diastereomer) 41 38(4-dimethylamino-4-phenyl-1-thiophen-2- 69 (329)yl-cyclohexyl)-dimethylamine (non-polar diastereomer) 58 46(4-butyl-4-dimethylamino-1-phenyl- 27 (303) cyclohexyl)-dimethylamine(non-polar diastereomer) 59 47 (4-butyl-4-dimethylamino-1-phenyl- 79(303) cyclohexyl)-dimethylamine (polar diastereomer) 62 60[4-(cyclopentyl-methyl)-4-dimethylamino- 51 (329)1-phenyl-cyclohexyl]-dimethylamine (non- polar diastereomer) 63 61[4-(cyclopentyl-methyl)-4-dimethylamino- 86 (329)1-phenyl-cyclohexyl]-dimethylamine (polar diastereomer) 72 71[4-(dimethylamino)-4-phenyl-1-[4- 36 (391)(trifluoromethyl)-phenyl]-cyclohexyl]- dimethylamine (polardiastereomer) 73 70 [4-dimethylamino-4-phenyl-1-[4- 68 (391)(trifluoromethyl)-phenyl]-cyclohexyl]- dimethylamine (non-polardiastereomer) 151 147 (1,4-diphenyl-4-pyrrolidin-1-yl- 34 (349)cyclohexyl)-dimethylamine (polar diastereomer) 152 148(1,4-diphenyl-4-pyrrolidin-1-yl- 45 (349) cyclohexyl)-dimethylamine(non-polar diastereomer)

Example 76[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer) Step 1 4-dimethylamino-4-phenyl-cyclohexanecarbaldehyde

Tert-BuOK (8.41 g, 75 mmol) dissolved in abs. THF (100 mL) was added indrops to a solution of (methoxymethyl)triphenyl phosphonium chloride(25.7 g, 75.0 mmol) in abs. THF (100 mL) at 0° C. in argon. Theresulting red solution was mixed after 30 min at 0° C. with a solutionof 4-dimethylamino-4-phenyl cyclohexanone (10.9 g, 50.0 mmol) in abs.THF (100 mL) and stirred overnight at RT. The solvent was removed in avacuum, the residue mixed with 1N sulphuric acid (150 mL) and stirredfor 2 h. The precipitate precipitated out during this was separated andthe filtrate (pH 1) washed with ether (6×100 mL). The aqueous solutionwas adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate(3×100 mL). The combined organic phases were dried over Na₂SO₄ andconcentrated to low volume in a vacuum.

Yield: 11.6 g (100%), brown oil

Diastereomer mixture 1:1

¹H-NMR (DMSO-d₆): 1.18 (1H, m); 1.59-1.91 (5H, m); 1.92 (6H, s); 2.36(3H, m); 7.23-7.38 (5H, m); 9.48 (0.5H, s); 9.62 (0.5H, s).

Step 2 4-dimethylamino-1-methyl-4-phenyl-cyclohexane carbaldehyde

A solution of the title compound from step 1 (11.6 g, 50.0 mmol) in abs.dichloromethane (200 mL) was mixed with tert-BuOK (6.50 g, 58.0 mmol)and methyl iodide (3.42 mL, 55.0 mmol) at 0° C. in argon. After 30 minthe batch was heated to RT and then stirred overnight (solid separatedout). The reaction mixture was washed with water and saturated NaClsolution (50 mL), dried over Na₂SO₄, concentrated to low volume in avacuum and the remaining residue purified by flash chromatography withethyl acetate/MeOH 20:1.

Yield: 5.90 g (48%)

¹H-NMR (DMSO-d₆): 0.83 (1.5H, s); 1.00 (1.5H, s); 1.08 (1H, m);1.55-1.82 (5H, m); 1.88 (3H, s); 1.92 (3H, s); 2.14-2.32 (2H, m); 7.27(5H, m); 9.36 (0.5H, s); 9.45 (0.5H, s).

Step 3 4-dimethylamino-1-methyl-4-phenyl-cyclohexane carbaldehyde oxime

A solution of the title compound of step 2 (5.90 g, 24.0 mmol) andhydroxylamine hydrochloride (2.50 mg, 36.0 mmol) in abs. ethanol (100mL) were mixed with Amberlyst A 21 (17.0 g) and stirred for 20 h at RT.The ion exchanger was filtered off, the solution concentrated to lowvolume and the residue made alkaline with 1N NaOH. The aqueous phase wasextracted with ethyl acetate, dried over Na₂SO₄ and concentrated to lowvolume in a vacuum.

Yield: 6.25 g (100%)

Step 4 [4-aminomethyl-4-methyl-1-phenylcyclohexyl]-dimethylamine

Lithium aluminium hydride (1.82 g, 48.0 mmol) was suspended in abs. THF(200 mL) in argon, mixed in drops with a solution of the title compoundfrom step 3 (6.25 g, 24.0 mmol) in abs. THF (20 mL) and boiled for 4 hwith reflux. The batch was then hydrolysed with water (20 mL) at 10° C.and filtered off over diatomaceous earth. The THF was removed in avacuum, the residue adjusted to pH 11 with 1N NaOH and extracted withethyl acetate. The combined organic phases were dried over Na₂SO₄,concentrated to low volume in a vacuum and the remaining residueseparated by flash chromatography with MeOH+1% NH₃.

Yield: 1.44 g (24%, non-polar diastereomer)

¹H-NMR (DMSO-d₆): 0.86 (3H, s); 1.03 (2H, m); 1.29 (2H, m); 1.84 (2H,m); 1.91 (6H, s); 2.10 (2H, m); 2.16 (2H, s); 7.24 (1H, m); 7.32 (4H,m).

Yield: 1.53 g (26%, polar diastereomer)

¹H-NMR (DMSO-d₆): 0.72 (3H, s); 1.00 (2H, m); 1.49 (2H, m); 1.83 (2H,m); 1.90 (6H, s); 2.05 (2H, m); 2.39 (2H, s); 7.23 (1H, m); 7.34 (4H,m).

Step 5[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

Indole-3 aldehyde (203 mg, 1.4 mmol) and the non-polar diastereomer fromstep 4 (345 mg, 1.4 mmol) were dissolved in abs. THF (10 mL), mixed withNa₂SO₄ (2.0 g) and stirred for 24 h at RT. Dichloroethane (10 mL) andsodium triacetoxyboron hydride (423 g, 2.0 mmol) were then added andstirred a further 24 h at RT. For work up the solvent was removed in avacuum, the residue mixed with EE (20 mL), water (20 mL) and 10%sulphuric acid (to pH 1) and the phases separated. The aqueous phase wasadjusted to pH 11 with 5N NaOH and extracted three times with ethylacetate. The combined organic phases were dried over Na₂SO₄,concentrated to low volume in a vacuum and the remaining residuepurified by flash chromatography with ethyl acetate/MeOH 1:1+1% NH₃.

Yield: 397 mg (76%), porous solid

¹H-NMR (DMSO-d₆): 0.92 (3H, s); 1.14 (2H, m); 1.32 (2H, m); 1.89 (8H,bs); 2.05 (2H, m); 2.22 (2H, s); 3.75 (2H, s); 6.9-7.54 (10H, m); 10.75(1H, s).

Example 77[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer)

Indole-3 aldehyde (203 mg, 1.4 mmol) and the polar diastereomer fromExample 76, step 4 (345 mg, 1.4 mmol) were dissolved in abs. THF (10mL), mixed with Na₂SO₄ (2.0 g) and stirred for 24 h at RT.Dichloroethane (10 mL) and sodium triacetoxyboron hydride (423 g, 2.0mmol) were then added and stirred a further 24 h at RT. For work up thesolvent was removed in a vacuum, the residue mixed with ethyl acetate(20 mL), water (20 mL) and 10% sulphuric acid (to pH 1) and the phasesseparated. The aqueous phase was adjusted to pH 11 with 5N NaOH andextracted three times with ethyl acetate. The combined organic phaseswere dried over Na₂SO₄, concentrated to low volume in a vacuum and theremaining residue purified by flash chromatography with ethylacetate/MeOH (1:1+1% NH₃).

Yield: 370 mg (70%)

Melting point: 55-56° C.

¹H-NMR (DMSO-d₆): 0.78 (3H, s); 1.02 (2H, m); 1.57 (3H, m); 1.79 (2H, m)1.86 (6H, s); 2.02 (2H, m); 2.44 (2H, s); 3.89 (2H, s); 6.97 (1H, t);7.06 (1H, t); 7.22-7.32 (7H, m); 7.64 (1H, d); 10.82 (1H, s).

Example 78[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

A solution of the title compound from Example 76 (300 mg, 0.8 mmol) andformalin (1.2 mL, 37% aqueous solution) in acetonitrile (10 mL) wasmixed in portions with sodium cyanoboron hydride (201 mg, 3.2 mmol) andstirred for 2 h at RT. Conc. acetic acid was then added until a neutralreaction occurred and the mixture stirred for 45 h at RT. For work upthe solvent was removed in a vacuum, the residue taken up in 2N NaOH (10mL) and then extracted with ether (3×20 mL). The organic solution wasdried over Na₂SO₄ and concentrated to low volume in a vacuum. Theremaining residue was purified by flash chromatography with ethylacetate/MeOH (1:1).

Yield: 189 mg (56%)

According to LMR and LCMS this was a hydroxymethyl compound that wasdissolved in 1N NaOH (2 mL) and THF (2 mL) and boiled for 2 h withreflux. The mixture was then extracted with ether (2×20 mL). The organicsolution was dried over Na₂SO₄ and concentrated to low volume in avacuum. The remaining residue was purified by flash chromatography withEE/MeOH (1:1+1% NH₃).

Yield: 119 mg (38%)

¹H-NMR (CDCl₃): 1.04 (3H, s); 1.32 (4H, m); 1.87 (2H, m); 2.05 (6H, s)2.14 (2H, s); 2.15 (3H, s); 2.34 (2H, m); 3.63 (2H, s); 6.78 (1H, s);7.08 (1H, t); 7.17 (1H, t); 7.30-7.41 (6H, m); 7.62 (1H, d); 7.99 (1H,s).

Example 79[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer)

A solution of the title compound from Example 77 (300 mg, 0.8 mmol) andformalin (1.2 mL, 37% aqueous solution) in acetonitrile (10 mL) wasmixed in portions with sodium cyanoboron hydride (201 mg, 3.2 mmol) andstirred for 2 h at RT. Conc. acetic acid was then added until a neutralreaction occurred and stirred for 45 h at RT. For work up the solventwas removed in a vacuum, the residue taken up in 2N NaOH (10 mL) andthen extracted with ether (3×20 mL). The organic solution was dried overNa₂SO₄ and concentrated to low volume in a vacuum. The remaining residuewas purified by flash chromatography with EE/MeOH (1:1.5 mL), acolourless solid precipitated out and this was separated. According toNMR and LCMS this was the hydroxymethyl compound.

The mother liquor was concentrated to low volume (240 mg), this was alsothe hydroxymethyl compound.

Yield: 299 mg (89%)

The hydroxymethyl compound (240 mg, 0.57 mmol) was dissolved in 1N NaOH(2 mL) and THF (2 mL) and boiled for 2 h with reflux. The mixture wasthen extracted with ether (2×20 mL). The organic solution was dried overNa₂SO₄ and concentrated to low volume in a vacuum. The remaining residuewas purified by flash chromatography with EE/MeOH (1:1+1% NH₃).

Yield: 181 mg (82%)

¹H-NMR (CDCl₃): 0.88 (3H, s); 1.13 (2H, m); 1.74 (2H, m); 1.80 (4H, m)2.10 (6H, s); 2.29 (3H, s); 2.44 (2H, s); 3.78 (2H, s); 7.10-7.40 (9H,m); 7.85 (1H, d); 8.24 (1H, s).

Example 80[3-[[[4-(dimethylamino)-1-methyl-4-phenyl-cyclohexyl]-methyl-methyl-amino]-methyl]-1H-indol-1-yl]-methanol(polar diastereomer)

The hydroxymethyl compound was formed as intermediate product as part ofthe synthesis of Example 79.

Yield: 299 mg (89%)

¹H-NMR (CDCl₃): 0.41 (2H, m); 0.62 (2H, m); 0.65 (3H, s); 1.27 (2H, m)1.61 (2H, m); 1.75 (6H, s); 2.28 (2H, s); 2.47 (3H, s); 3.64 (2H, s);5.63 (2H, s); 7.01 (2H, m); 7.14-7.40 (7H, m); 7.76 (1H, d)

Example 86[4-[[4,6-bis(methylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

The title compound of Example 103 (200 mg, 0.31 mmol) was dissolved in a33% methylamine solution in ethanol (2 mL) and stirred in the microwavefor 30 min at 100° C. and 60 min at 120° C. The precipitated precipitatewas aspirated and dried in a vacuum.

Yield: 89 mg (64%)

Melting point: 250-252° C.

¹H-NMR (DMSO): 1.65 (2H, m); 1.96 (6H, s); 2.41 (4H, m); 2.60 (6H, s);3.06 (5H, m); 6.21 (2H, m); 7.16-7.43 (10H, m).

Example 87[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

As part of the synthesis of the title compound of Example 86 the motherliquor was concentrated to low volume in a vacuum and the remainingresidue was purified by flash chromatography with ethyl acetate.

Yield: 25 mg (15%)

Melting point: 181-182° C.

¹H-NMR (DMSO), temp: 100° C.: 1.70 (2H, m); 1.99 (6H, s); 2.24 (2H, m);2.38 (2H, m); 2.56 (2H, m); 2.67 (3H, d); 2.96 (3H, s); 3.76 (3H, s);6.71 (1H, m); 6.98 (3H, m); 7.15-7.38 (10H, m).

The following compounds were obtained following a specification such asdescribed in Examples 86 and 87 except that the educts listed in Table1-4 were used.

TABLE 1-4 Cy Method (%)/ Ex. according MS No. Educt to Product (m/z) 90Ex. Ex. 86 [4-[[4,6-bis(methylamino)- 13 (446) 100[1,3,5]triazin-2-yl]-methyl-amino]- 1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer) 91 Ex. Ex. 87[4-[[4-(4-methoxy-phenoxy)-6- 59 (539) 100methylamino-[1,3,5]triazin-2-yl]- methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer)

Example 94[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(polar diastereomer) Step 14-(dimethylamino)-4-(3-fluorophenyl)-1-(3-methyl-1H-indol-2-yl)cyclohexanol(non-polar and polar diastereomer)

n-butyl lithium (8.39 mmol, 3.35 ml, 2.5M in hexane) was slowly added toa solution of skatole (1.00 g, 7.62 mmol) in absolute tetrahydrofuran(25 ml) in an argon atmosphere at −78° C. A colourless precipitate wasformed. After 10 min the solution was heated to room temperature. Carbondioxide was then introduced into the reaction mixture for approx. 3 min.A colourless solution was formed. After 5 min the volatile constituentswere completely removed in a vacuum at room temperature (water bathtemperature ≦30° C.). The colourless solid residue was again dissolvedin absolute tetrahydrofuran (20 ml). The light yellow reaction mixturewas cooled to −78° C. and tert-butyl lithium (8.39 mmol, 5.59 ml, 1.5Min pentane) was added in drops. An orange solution was formed. This wasstirred for 1 h at −20° C. and then cooled to −78° C.4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone [1.97 g, 8.39 mmol, inabsolute tetrahydrofuran (20 ml)] was then added in drops and theresulting solution stirred for 2 h. Saturated aqueous ammonium chloridesolution (50 ml) was then added in drops to the reaction mixture,stirred for 10 min, the mixture heated to 0° C. and stirred for 20 min.2N aqueous hydrogen chloride solution (50 ml) was added thereto andstirred for 10 min (light gas development). The pH value of the milkysuspension was then basified with saturated sodium hydrogencarbonatesolution (50 ml) and 5N sodium hydroxide solution (20 ml). After 10 minthe phases were separated. The organic phase contained a colourlesssolid. The phases were separated. The aqueous phase was extracted withdichloromethane/methanol 20:1 (3×50 ml). The organic solutions werecombined. The volatile constituents were completely removed in a vacuum.The remaining light brown powder was extracted with methanol (5×75 ml).The residue was exclusively composed of the non-polar diastereoisomer6b/7b (450 mg, 1.23 mmol, 16%). The extracts were concentrated until dryin a vacuum. The residue was taken up in methanol (approx. 30 ml). Alight-coloured solid did not dissolve. This was separated by means of afritted glass filter and then dried in a vacuum. 980 mg (2.67 mmol, 35%)of a colourless powder were obtained. This was composed of the twodiastereoisomers.

The mother liquor was separated by chromatography [silica gel 60 (150g); trichloromethane/ethanol 50:1 (500 ml), 19:1 (500 ml), 9:1 (300 ml),5:1 (300 ml), 1:1 (300 ml), 0.5% triethylamine in each case, betterbegin with trichloromethane/ethanol 100:1]. The obtained fractions ofthe two diastereoisomers had to be recrystallised from methanol. 93 mg(0.25 mmol, 3%) of the more non-polar diastereoisomer (mp 197-202° C.)and 146 mg (0.40 mmol, 5%) of the more polar diastereoisomer (179-188°C.) were obtained.

13C{1H}-NMR (101 MHz, DMSO-D6, δ ppm, more non-polar diastereoisomer):9.5 (1C), 28.4 (2C), 32.5 (2C), 37.8 (2C), 58.2 (1C, br), 69.4 (1C),102.7 (1C), 111.0 (1C), 113.0 (1C, d, J=21 Hz), 113.4 (1C, d, J=21 Hz),117.3 (1C), 117.8 (1C) 119.9 (1C), 122.6 (1C, d, J=2 Hz), 128.9 (1C, J=8Hz), 129.8 (1C), 133.9 (1C), 142.1 (1C, br), 142.7 (1C, d, J=5 Hz),161.9 (1C, d, J=242 Hz)

13C{1H}-NMR (101 MHz, DMSO-D6, δ ppm, more polar diastereoisomer): 9.0(1C), 26.9 (2C, br), 33.5 (2C), 37.6 (2C), 55.9 (1C, br), 68.5 (1C),102.3 (1C), 110.9 (1C), 113.5 (1C, sbr), 115.8 (1C, sbr), 117.2 (1C),117.8 (1C) 120.0 (1C), 125.0 (1C, sbr), 126.6 (1C), 130.0 (1C, br),133.7 (1C), 141.1 (1C, br), 162.4 (1C, d, J=244 Hz), n.b. (1C)

Step 21-(3-fluorophenyl)-4-(1H-indol-2-yl)-7,7-dimethyl-7-azoniabicyclo[2.2.1]heptanefluoride

The alcohol from step 1 (both diastereoisomers, 2.20 g, 6.00 mmol) wassuspended in absolute dichloromethane (50 ml) at −78° C. Triethylamine(3.65 g, 36.02 mmol, 4.99, 0.73 g/ml), DMAP (16 mg, 0.12 mmol) and DAST(2.90 g, 18.01 mmol, 2.36 ml, 1.23 g/ml) were added one after the other.The solution was stirred for 1 h at −78° C. The reaction mixture wasthen heated to room temperature within 10 h (overnight). Saturatedsodium hydrogencarbonate solution (50 ml) was then added and stirred for15 min (until the gas development was finished). Sodium hydroxidesolution (5N, 20 ml) was then added and stirred for 10 min. The phaseswere separated.

The red-brown organic phase was concentrated until dry in a vacuum. Thebrown solid obtained was then dissolved in methanol (50 ml). The aqueousphase was also concentrated until dry in a vacuum. The light-colouredresidue was extracted with methanol (5×75 ml). The combined methanolsolutions were concentrated until dry in a vacuum. The residue wasextracted firstly with dichloromethane (2×30 ml) and then with methanol(5×75 ml). A light-coloured solid remained. The methanol extracts wereconcentrated until dry in a vacuum. There remained 1.20 g (3.26 mmol,54%) of the product as light-coloured solid. The dichloromethaneextracts were concentrated until dry in a vacuum. The residue was takenup in methanol (5 ml) and left to stand. A white solid separated out. Afurther 0.43 g (1.16 mmol, 19%) of the product (mp 175° C.) was thusobtained.

¹³C{¹H}-NMR (101 MHz, DMSO-D₆, δ ppm): 11.2 (1C), 29.8 (2C), 30.3 (2C),40.6 (2C), 81.2 (1C, d, J=2 Hz), 83.2 (1C), 111.5 (1C), 114.4 (1C),116.7 (1C, d, J=23 Hz), 117.6 (1C, d, J=21 Hz), 119.11 (1C), 119.13 (1C)121.7 (1C), 123.4 (1C), 125.6 (1C, J=3 Hz), 128.8 (1C), 131.0 (1C, d,J=8 Hz), 132.2 (1C, d, J=7 Hz), 135.8 (1C), 162.3 (1C, d, J=244 Hz)

Step 3[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(polar diastereomer)

The title compound from step 2 (500 mg, 1.36 mmol) was suspended inacetonitrile/methanol (1:1.20 ml). Dimethylamine (2M in tetrahydrofuran,14 ml, 27.15 mmol) was then added and stirred for 2 d at roomtemperature. The solution was stirred for 6 h at 80° C. (oil bathtemperature), then applied to coarse silica gel and separated by flashchromatography [silica gel 60 (150 g); trichloromethane/ethanol 50:1(1000 ml), 19:1 (500 ml), 9:1 (1000 ml), 0.5% triethylamine in eachcase]. The more non-polar diastereoisomer was firstly isolated. Inaddition, 250 mg of a solid mixture were isolated. The solid mixture wasdissolved in methanol (10 ml), 50 mg of potassium hydroxide added andstirred for 10 min. The volatile constituents were removed completely ina vacuum. The light-coloured residue was extracted with ethyl acetate(3×20 ml). The volatile constituents were released from the extracts ina vacuum. 135 mg (0.34 mmol, 25%) of the more polar diastereoisomer (mp65-73° C.) were isolated.

¹³C{¹H}-NMR (101 MHz, DMSO-D₆, δ ppm, more polar diastereoisomer): 10.7(1C), 28.8 (2C, br), 29.3 (2C, br), 37.7 (2C), 38.7 (2C), 58.7 (1C, br),60.5 (1C, br), 107.0 (1C, br), 110.5 (1C), 112.9 (1C, d, J=21 Hz), 113.7(1C, d, J=21 Hz), 117.5 (1C), 117.7 (1C), 120.4 (1C), 122.9 (1C, br),128.9 (1C, d, J=8 Hz), 129.0 (1C), 132.5 (1C, sbr), 134.5 (1C), 141.4(1C, br), 161.9 (1C, d, J=243 Hz)

Example 97[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(non-polar diastereomer)

The non-polar diastereomer was also formed during the synthesis of thetitle compound of Example 94, step 3. 152 mg (0.39 mmol, 29%) (mp126-132° C.) were isolated.

¹³C{¹H}-NMR (101 MHz, DMSO-D₆, δ ppm, more non-polar diastereoisomer):10.7 (1C), 29.6 (2C, br), 29.7 (2C, br), 37.8 (2C), 38.7 (2C), 60.0 (1C,br), 60.6 (1C, br), 107.0 (1C, br), 110.5 (1C), 113.0 (1C, d, J=21 Hz),114.2 (1C, d, J=21 Hz), 117.5 (1C), 117.8 (1C), 120.4 (1C), 123.5 (1C,br), 129.1 (1C), 129.1 (1C, d, J=6 Hz), 132.2 (1C, br), 134.6 (1C),140.4 (1C, br), 162.2 (1C, d, J=242 Hz)

The following compounds were obtained following a specification such asdescribed in Examples 94 and 97 except that the educts listed in Table1-5 were used.

TABLE 1-5 Cy* (%)/ Ex. MS No. Indole Ketone Amine Product (m/z) 35Skatole BB-A Dimethylamine [4-(dimethylamino)-4-(3-methyl- 27 (376)1H-indol-2-yl)-1-phenyl- cyclohexyl]-dimethylamine (polar diastereomer)36 Skatole BB-A Dimethylamine [4-(dimethylamino)-4-(3-methyl- 25 (376)1H-indol-2-yl)-1-phenyl- cyclohexyl]-dimethylamine (non- polardiastereomer) 53 Skatole BB-A Pyrrolidinedimethyl-[4-(3-methyl-1H-indol- 17 (402)2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-amine dihydrochloride(polar diastereomer) 54 Skatole BB-A Pyrrolidinedimethyl-[4-(3-methyl-1H-indol- 48 (402)2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-amine (non-polardiastereomer) 56 Skatole BB-A Acetidine [4-(acetidin-1-yl)-4-(3-methyl-19 (388) 1H-indol-2-yl)-1-phenyl- cyclohexyl]-dimethylamine (non- polardiastereomer) 82 Skatole BB-A Methylamine [4-dimethylamino-1-(3-methyl-26 (362) 1H-indol-2-yl)-4-phenyl- cyclohexyl]-methylamine (polardiastereomer) 83 Skatole BB-A Methylamine [4-dimethylamino-1-(3-methyl-22 (362) 1H-indol-2-yl)-4-phenyl- cyclohexyl]-methylamin (non- polardiastereomer) 84 Skatole BB-A Benzylamine benzyl-[4-dimethylamino-1-(3-12 (438) methyl-1H-indol-2-yl)-4-phenyl- cyclohexyl]-amine; 2-hydroxy-propane-1,2,3-tricarboxylic acid 95 Skatole BB-B Acetidine4-(acetidin-1-yl)-1-(3- 33 (406) fluorophenyl)-N,N-dimethyl-4-(3-methyl-1H-indol-2- yl)cyclohexanamine (non-polar diastereomer) 96Skatole BB-B Acetidine 4-(acetidin-1-yl)-1-(3-  4 (406)fluorophenyl)-N,N-dimethyl-4- (3-methyl-1H-indol-2- yl)cyclohexanamine(polar diastereomer) 108 Skatole BB-B Pyrrolidine[1-(3-fluorophenyl)-4-(3-methyl- 36 (420)1H-indol-2-yl)-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (non- polardiastereomer) 109 Skatole BB-B Pyrrolidine[1-(3-fluorophenyl)-4-(3-methyl- 29 (420)1H-indol-2-yl)-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (polardiastereomer) 110 Skatole BB-B Methylamine [1-(3-fluorophenyl)-4- 10(380) methylamino-4-(3-methyl-1H- indol-2-yl)-cyclohexyl]-dimethyl-amine 111 Skatole BB-A Piperidine dimethyl-[4-(3-methyl-1H-indol- 23(416) 2-yl)-1-phenyl-4-piperidin-1-yl- cyclohexyl]-amine (non-polardiastereomer) 112 Skatole BB-B Piperidine[1-(3-fluorophenyl)-4-(3-methyl-  4 (434)1H-indol-2-yl)-4-piperidin-1-yl- cyclohexyl]-dimethylamine (polardiastereomer) 133 Skatole BB-B Piperidine[1-(3-fluorophenyl)-4-(3-methyl- 35 (434)1H-indol-2-yl)-4-piperidin-1-yl- cyclohexyl]-dimethylamine (non- polardiastereomer) 113 IN-A BB-A Dimethylamine[4-(dimethylamino)-4-(5-fluoro- 41 (394) 3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl- amine (polar diastereomer) 125 IN-A BB-ADimethylamine [4-(dimethylamino)-4-(5-fluoro- 27 (394)3-methyl-1H-indol-2-yl)-1- phenyl-cyclohexyl]-dimethyl- amine (non-polardiastereomer) 126 IN-A BB-A Pyrrolidine [4-(5-fluoro-3-methyl-1H-indol-42 (420) 2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine(non- polar diastereomer) 132 IN-A BB-A Pyrrolidine[4-(5-fluoro-3-methyl-1H-indol- 38 (420)2-yl)-1-phenyl-4-pyrrolidin-1-yl- cyclohexyl]-dimethylamine (polardiastereomer) 134 IN-A BB-B Acetidine [4-(acetidin-1-yl)-4-(5-fluoro-3-55 (406) methyl-1H-indol-2-yl)-1-(3- fluorophenyl)-cyclohexyl]-dimethylamine (polar diastereomer) 135 IN-A BB-B Acetidine[4-(acetidin-1-yl)-4-(5-fluoro-3- 28 (406) methyl-1H-indol-2-yl)-1-(3-fluorophenyl)-cyclohexyl]- dimethylamine (non-polar diastereomer) 136IN-A BB-A Morpholine [4-(5-fluoro-3-methyl-1H-indol- 30 (436)2-yl)-4-morpholin-4-yl-1-phenyl- cyclohexyl]-dimethylamine (polardiastereomer) 140 IN-A BB-A Morpholine [4-(5-fluoro-3-methyl-1H-indol-15 (436) 2-yl)-4-morpholin-4-yl-1-phenyl- cyclohexyl]-dimethylamine(non- polar diastereomer) 137 IN-A BB-A Methylamine[4-(5-fluoro-3-methyl-1H-indol- 11 (380) 2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethylamine (non- polar diastereomer) 138 IN-A BB-AMethylamine [4-(5-fluoro-3-methyl-1H-indol- 11 (380)2-yl)-4-methylamino-1-phenyl- cyclohexyl]-dimethylamine (polardiastereomer) 139 IN-A BB-C Methylamine dimethyl-[4-methylamino-4-(3- 21(368) methyl-1H-indol-2-yl)-1- thiophen-2-yl-cyclohexyl]-amine (polardiastereomer) 150 IN-A BB-C Methylamine dimethyl-[4-methylamino-4-(3- 46(368) methyl-1H-indol-2-yl)-1- thiophen-2-yl-cyclohexyl]-amine(non-polar diastereomer) 159 IN-A BB-B Cyclohexylmethyl[4-(cyclohexyl-methylamino)-1- 43 (462) amine(3-fluorophenyl)-4-(3-methyl- 1H-indol-2-yl)-cyclohexyl]- dimethylamine(non-polar diastereomer) 160 IN-A BB-B Cyclopentylamine[4-(cyclopentylamino)-1-(3- 36 (434) fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl- amine (non-polar diastereomer) 161IN-A BB-B Aniline [4-anilino-1-(3-fluorophenyl)-4- 28 (381;(3-methyl-1H-indol-2-yl)- M + 1 − NMe₂ − Me) cyclohexyl]-dimethylamine162 IN-A BB-B 4-Aminopyridine [1-(3-fluorophenyl)-4-(3-methyl-  5 (443)1H-indol-2-yl)-4-(pyridin-4- ylamino)-cyclohexyl]-dimethyl- amine *forthe last step. Indoles: Skatole 5-fluoro-3-methyl-1H-indole (IN-A)Ketones: 4-dimethylamino-4-phenylcyclohexanone (BB-A)4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone (BB-B)4-(dimethylamino)-4-(thiophen-2-yl)cyclohexanone (BB-C)

The following compounds were obtained following a specification such asdescribed in Example 86 except that amines and educts such as listed inTable 1-6 were used, and also in the case of high-boiling amines theoperation was conducted without solvent.

TABLE 1-6 Cy (%)/ Ex. MS No. Educt Amine Product (m/z) 129 Ex. 91Piperidine dimethyl-[4-[methyl-(4- 89 (500)methylamino-6-piperidin-1-yl- [1,3,5]triazin-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereomer) 141 Ex. 87 Aniline[4-[(4-anilino-6-methylamino- 38 (508)[1,3,5]triazin-2-yl)-methyl-amino]- 1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereomer) 142 Ex. 91 N-[4-[[4-(isopropyl-methyl-amino)-6- 44 (488) Isopropylmethylaminemethylamino-[1,3,5]triazin-2-yl]- methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer) 143 Ex. 91 Aniline[4-[(4-anilino-6-methylamino- 84 (508)[1,3,5]triazin-2-yl)-methyl-amino]- 1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereomer) 144 Ex. 91 Benzylamine[4-[[4-(benzylamino)-6- 90 (522) methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl- cyclohexyl]-dimethylamine (polardiastereomer) 145 Ex. 91 Butylamine [4-[(4-butylamino-6-methylamino- 86(488) [1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl- amine (polar diastereomer)

Example 100[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]-triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer)

A solution of the title compound from Example 9 (616 mg, 2.0 mmol) and4-methoxyphenyl cyanate (895 mg, 6.0 mmol) in abs. acetone (20 mL) wasstirred for 3 d at RT. The solvent was then removed in a vacuum and theremaining residue purified by flash chromatography with ethylacetate/MeOH (20:1).

Yield: 1.16 g (92%)

¹H-NMR (CDCl₃): 1.77 (4H, m); 1.89 (6H, s); 2.50 (4H, m); 3.07 (3H, s);3.76 (6H, s); 6.84-7.36 (18H, m).

Example 103[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

A solution of the title compound from Example 8 (154 mg, 0.5 mmol) and4-methoxyphenyl cyanate (224 mg, 1.5 mmol) in abs. acetone (10 mL) wasstirred for 3 d at RT. The solvent was then removed in a vacuum and theremaining residue purified by flash chromatography with ethylacetate/cyclohexane (1:1).

Yield: 226 mg (72%)

¹H-NMR (CDCl₃): 1.80 (4H, m); 1.96 (6H, s); 2.28 (2H, m); 2.43 (2H, m);3.04 (3H, s); 3.80 (6H, s); 6.89-7.40 (18H, m).

The following compounds were obtained following a specification such asdescribed in Example 24 except that acylation and sulphonylationreagents and amines such as listed in Table 1-7 were used.

TABLE 1-7 Cy (%)/ Ex. MS No. Amine Reagent Product (m/z) 25 Ex. 8 Acetylchloride N-(4-dimethylamino-1,4-diphenyl- 68 (351)cyclohexyl)-N-methyl-acetamide (non-polar diastereomer) 26 Ex. 9 Methanesulphonyl N-(4-dimethylamino-1,4-diphenyl- 36 (387) chloridecyclohexyl)-N-methyl- methanesulphonic acid amide (polar diastereomer)27 Ex. 9 Cinnamic acid chloride (E)-N-(4-dimethylamino-1,4- 90 (439)diphenyl-cyclohexyl)-N-methyl-3- phenyl-acrylamide (polar diastereomer)28 Ex. 9 Acetyl chloride N-(4-dimethylamino-1,4-diphenyl- 65 (351)cyclohexyl)-N-methyl-acetamide (polar diastereomer) 29 Ex. 8 Benzylisocyanate 3-benzyl-1-(4-dimethylamino-1,4- 79 (442)diphenyl-cyclohexyl)-1-methyl- urea (non-polar diastereomer) 30 Ex. 9Benzyl isocyanate 3-benzyl-1-(4-dimethylamino-1,4- 88 (442)diphenyl-cyclohexyl)-1-methyl- urea (polar diastereomer) 31 Ex. 8 Ethylisocyanate 1-(4-dimethylamino-1,4-diphenyl- 60 (380)cyclohexyl)-3-ethyl-1-methylurea (non-polar diastereomer) 32 Ex. 9 Ethylisocyanate 1-(4-dimethylamino-1,4-diphenyl- 100 (380) cyclohexyl)-3-ethyl-1-methylurea (polar diastereomer) 43 Ex. 42,Cinnamic acid chloride (E)-N-[[4-dimethylamino-4-(3- 96 (395) step 4fluorophenyl)-1-methyl- (non- cyclohexyl]-methyl]-3-phenyl- polar)acrylamide (non-polar diastereomer) 44 Ex. 42, (E)-2-phenylethene(E)-N-[[4-dimethylamino-4-(3- 68 (431) step 4 sulphonyl chloridefluorophenyl)-1-methyl- (non- cyclohexyl]-methyl]-2- polar) phenylethenesulphonamide (non- polar diastereomer) 45 Ex. 42, (E)-2-phenylethene(E)-N-[[4-dimethylamino-4-(3- 66 (431) step 4 sulphonyl chloridefluorophenyl)-1-methyl- (polar) cyclohexyl]-methyl]-2- phenylethenesulphonamide (polar diastereomer) 52 Ex. 9 Diphenyl acetyl chlorideN-[4-(dimethyl-amino)-1,4- 23 (337) diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-acetamide (polar diastereomer) 57 Ex. 8 Methane sulphonylN-(4-dimethylamino-1,4-diphenyl- 15 (387) chloridecyclohexyl)-N-methyl-methane sulphonamide (non-polar diastereomer) 64Ex. 60 Cinnamic acid chloride (E)-N-[4-(cyclopentyl-methyl)-4- 75 (445)dimethylamino-1-phenyl- cyclohexyl]-N-methyl-3-phenyl- acrylamide(non-polar diastereomer) 65 Ex. 61 Cinnamic acid chloride(E)-N-[4-(cyclopentyl-methyl)-4- 63 (445) dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl- acrylamide (polar diastereomer) 81 Ex. 82Cinnamic acid chloride (E)-N-[4-dimethylamino-1-(3- 17 (492)methyl-1H-indol-2-yl)-4-phenyl- cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereomer) 88 Ex. 8 Nicotinic acid chlorideN-[4-(dimethyl-amino)-1,4- 58 (414) hydrochloridediphenyl-cyclohexyl]-N-methyl- pyridine-3-carboxylic acid amide(non-polar diastereomer) 92 Ex. 9 1-methyl-1H-pyrazole-3-N-[4-(dimethyl-amino)-1,4- 93 (417) carboxylic acid chloridediphenyl-cyclohexyl]-N,1- dimethyl-1H-pyrazole-3- carboxylic acid amide(polar diastereomer) 98 Ex. 8 3-trifluoromethyl-N-(4-dimethylamino-1,4-diphenyl- 43 (481) benzoyl chloridecyclohexyl)-N-methyl-3- (trifluoromethyl)-benzamide (non- polardiastereomer) 99 Ex. 9 3-(trifluoromethyl)benzoylN-(4-dimethylamino-1,4-diphenyl- 67 (481) chloridecyclohexyl)-N-methyl-3- (trifluoromethyl)-benzamide (polar diastereomer)104 Ex. 8 4-methoxy-phenyl- N-(4-dimethylamino-1,4-diphenyl- 59 (443)carboxylic acid chloride cyclohexyl)-4-methoxy-N-methyl- benzamide(non-polar diastereomer) 105 Ex. 9 4-methoxy-phenyl-N-(4-dimethylamino-1,4-diphenyl- 90 (443) carboxylic acid chloridecyclohexyl)-4-methoxy-N-methyl- benzamide (polar diastereomer) 116 Ex. 83-fluorobenzoyl chloride N-(4-dimethylamino-1,4-diphenyl- 49 (431)cyclohexyl)-3-fluoro-N-methyl- benzamide (non-polar diastereomer) 117Ex. 9 3-fluorobenzoyl chloride N-(4-dimethylamino-1,4-diphenyl- 84 (431)cyclohexyl)-3-fluoro-N-methyl- benzamide (polar diastereomer) 165 Ex. 9Cyclohexane carboxylic N-(4-dimethylamino-1,4-diphenyl- 50 (419) acidchloride cyclohexyl)-N-methyl- cyclohexane carboxylic acid amide (polardiastereomer) 166 Ex. 9 Tetrahydro-pyrane-4-N-(4-dimethylamino-1,4-diphenyl- 30 (421) carboxylic acid chloridecyclohexyl)-N-methyl-tetrahydro- pyrane-4-carboxylic acid amide (polardiastereomer) 169 Ex. 9 1-methyl-piperidine-4-N-(4-dimethylamino-1,4-diphenyl- 79 (434) carboxylic acid chloridecyclohexyl)-N,1-dimethyl- piperidine-4-carboxylic acid amide (polardiastereomer)

The following compounds were obtained following a specification such asdescribed in Example 48, step 2 except that the amides such as listed inTable 1-8 were used.

TABLE 1-8 Ex. No. Amide Product Cy (%)/MS (m/z) 85 BB-1dimethyl-[4-[methyl-(pyridin- 37 (400) 3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereomer) 89 Ex. 89dimethyl-[4-[methyl-(pyridin- 73 (400) 3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine (non-polar diastereomer) 101 Ex. 92(4-dimethylamino-1,4- 71 (403) diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazol-3-yl)- methyl]-amine (polar diastereomer) 102 Ex.93 (4-dimethylamino-1,4- 67 (403) diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazol-3-yl)- methyl]-amine (non-polar diastereomer) 106Ex. 105 (4-dimethylamino-1,4- 85 (429) diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]- methylamine (polar diastereomer) 107 Ex. 104(4-dimethylamino-1,4- 77 (429) diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]- methylamine (non-polar diastereomer) 114 Ex. 99(4-dimethylamino-1,4- 81 (467) diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]- methyl]-amine (polar diastereomer) 115 Ex.98 (4-dimethylamino-1,4- 42 (467) diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]- methyl]-amine (non-polar diastereomer) 118Ex. 116 (4-dimethylamino-1,4- 98 (417) diphenyl-cyclohexyl)-[(3-fluorophenyl)-methyl]-methyl- amine (non-polar diastereomer) 119 Ex. 117(4-dimethylamino-1,4- 99 (417) diphenyl-cyclohexyl)-[(3-fluorophenyl)-methyl]-methyl- amine (polar diastereomer) 167 Ex. 165cyclohexyl-methyl-(4- 84 (405) dimethylamino-1,4-diphenyl-cyclohexyl)-methylamine (polar diastereomer) 168 Ex. 166(4-dimethylamino-1,4- 44 (407) diphenyl-cyclohexyl)-methyl-(tetrahydro-pyran-4-yl- methyl)-amine (polar diastereomer) 170 Ex. 169(4-dimethylamino-1,4- 93 (420) diphenyl-cyclohexyl)-methyl-[(1-methyl-piperidin-4-yl)- methyl]-amine (polar diastereomer) BB-1:N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-nicotinamide Asolution of the title compound from Example 9 (308 mg, 1.0 mmol) andtriethylamine (334 μl, 2.4 mmol) in abs. THF (15 mL) was mixed withnicotinic acid chloride hydrochloride (214 mg, 1.2 mmol) and stirred for3 d at RT. The solvent was then removed in a vacuum, the remainingresidue dissolved in ethyl acetate, washed with saturated NaHCO₃solution and saturated NaCl solution, dried over Na₂SO₄ and purified byflash chromatography with ethyl acetate/MeOH 1:1. Yield: 300 mg (73%),porous solid ¹H-NMR (DMSO): 1.67 (2 H, m); 1.92 (2 H, m); 1.98 (8 H, s);2.48 (2 H, m); 2.80 (3 H, s); 7.15-7.41 (10 H, m); 7.52 (1 H, m); 7.92(1 H, m); 8.69 (2 H, m).

Example 1202-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol(polar diastereomer) Step 1[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-methyl acetate

The title compound from Example 9 (463 mg, 1.50 mmol) was provided inabs. DMF (10 mL) and mixed with potassium carbonate (347 mg, 1.65 mmol)and methyl bromoacetate (157 μL, 1.65 mmol). The batch was stirred for 3d at room temperature and then concentrated until dry in a vacuum. Theresidue was taken up in dichloromethane (50 mL) and washed with water(2×50 mL) and saturated NaCl solution (50 mL), the organic phase wasthen dried over Na₂SO₄ and concentrated to low volume in a vacuum. Theresidue was purified by means of flash chromatography with ethylacetate/methanol (9:1).

Yield: 338 mg (59%)

¹H-NMR (DMSO-d₆): 1.73 (4H, m); 1.96 (6H, s); 2.04 (3H, s); 2.31 (4H,m); 2.96 (2H, m); 3.58 (3H, s); 7.17 (2H, m); 7.28 (8H, m).

Step 22-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol(polar diastereomer)

The title compound from step 1 (322 mg, 0.85 mmol) was dissolved in abs.THF (15 mL), mixed with LiAlH₄ (64 mg, 1.69 mmol) in argon and boiledfor 3 h with reflux. The batch was then cooled to room temperature,mixed with THF (10 mL) and H₂O (5 mL) with ice cooling and subsequentlystirred for 30 min. The batch was filtered via a fritted glass filterwith diatomaceous earth and the diatomaceous earth was subsequentlywashed with dichloromethane (50 mL). The combined filtrates wereconcentrated to low volume in a vacuum. The raw product was mixed withwater (10 mL) and extracted with dichloromethane (3×20 mL). The organicphase was dried over Na₂SO₄ and concentrated to low volume in a vacuum.The residue was purified by means of flash chromatography with ethylacetate/methanol (1:1).

Yield: 213 mg (71%)

¹H-NMR (DMSO-d₆): 1.72 (4H, m); 1.95 (6H, s); 2.06 (3H, s); 2.19 (2H,m); 2.29 (4H, m); 3.39 (2H, m); 4.25 (1H, m); 7.17 (2H, m); 7.27 (8H,m).

Example 1222-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-acetamide(polar diastereomer)

The title compound from Example 66 (293 mg, 0.8 mmol) was dissolved inabs. DMF (10 mL) and mixed with N-hydroxybenzotriazole hydrate (135 mg,0.88 mmol) and TEA (1.11 mL, 8.0 mmol). After 30 minN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (460 mg,2.4 mmol) and methylamine (440 μL, 0.88 mmol, 2M solution in THF) wereadded and stirred overnight at RT. The solution was filtered andconcentrated to low volume in a vacuum. By flash chromatography withethyl acetate/MeOH (4:1→1:1), a salt of the product was obtained, whichwas released with 1N NaOH, extracted with CH₂Cl₂, dried over Na₂SO₄ andthe solvent removed in a vacuum.

Yield: 182 mg (60%)

¹H-NMR (DMSO): 1.47 (2H, m); 1.96 (7H, s); 1.99 (3H, s); 2.24 (3H, m);2.42 (2H, m); 2.64 (6H, m); 7.24 (9H, m); 7.60 (1H, m).

The following compounds were obtained following a specification such asdescribed in Example 122 except that the acids and amines listed inTable 1-9 were used.

TABLE 1-9 Ex. Cy (%)/ No. Educt Amine Product MS (m/z) 121 Ex. 66Dimethylamine 2-[(4-dimethylamino-1,4- 17 (394) diphenyl-cyclohexyl)-methyl-amino]-N,N- dimethyl-acetamide (polar diastereomer) 123 Ex. 67Dimethylamine 2-[(4-dimethylamino-1,4- 55 (380) diphenyl-cyclohexyl)-methyl-amino]-N,N- dimethyl-acetamide (non-polar diastereomer) 124 Ex.67 Methylamine 2-[(4-dimethylamino-1,4- 55 (394) diphenyl-cyclohexyl)-methyl-amino]-N- methyl-acetamide (non-polar diastereomer)

Example 1272-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol(non-polar diastereomer) Step 1

4[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-methyl acetate

The title compound from Example 8 (463 mg, 1.50 mmol) was provided inabs. DMF (10 mL) and mixed with potassium carbonate (347 mg, 1.65 mmol)and methyl bromoacetate (157 μL, 1.65 mmol). The batch was stirred for 3d at room temperature and then concentrated until dry in a vacuum. Theresidue was taken up in dichloromethane (50 mL) and washed with water(2×50 mL) and saturated NaCl solution (50 mL), the organic phase wasdried over Na₂SO₄ and concentrated to low volume in a vacuum. Theresidue was purified by flash chromatography with ethyl acetate/methanol(9:1).

Yield: 234 mg (41%)

¹H-NMR (DMSO-d₆): 1.72 (4H, m); 1.84 (6H, s); 1.93 (3H, s); 2.27 (4H,m); 2.87 (2H, m); 3.48 (3H, s); 7.26 (2H, m); 7.38 (8H, m).

Step 22-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol(non-polar diastereomer)

The title compound from step 1 (228 mg, 0.60 mmol) was dissolved in abs.THF (10 mL), mixed with LiAlH₄ (45 mg, 1.20 mmol) in argon and boiledfor 3 h with reflux. The batch was then cooled to room temperature,mixed with THF (10 mL) and H₂O (5 mL) with ice cooling and subsequentlystirred for 30 min. The batch was filtered via a fritted glass filterwith diatomaceous earth and the diatomaceous earth subsequently washedwith dichloromethane (50 mL). The combined filtrates were concentratedto low volume in a vacuum. The raw product was mixed with water (10 mL)and extracted with dichloromethane (3×20 mL), the organic phase was thendried over Na₂SO₄ and concentrated to low volume in a vacuum. Theresidue was purified by flash chromatography with ethyl acetate/methanol(9:1→4:1).

Yield: 174 mg (82%)

Melting point: 144-149° C.

¹H-NMR (DMSO-d₆): 1.73 (4H, m); 1.84 (6H, s); 1.96 (3H, s); 2.09 (2H,m); 2.27 (4H, m); 3.23 (2H, m); 4.14 (1H, m); 7.25 (2H, m); 7.38 (8H,m).

Example 128[4-[[4,6-bis(dimethylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer) Step 1N-(4,6-dichloro[1,3,5]triazin-2-yl)-N,N′,N′-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine

Cyanuric chloride (86 mg, 0.49 mmol) was provided in abs. THF (3 mL),mixed with a solution of the title compound from Example 8 (150 mg, 0.49mmol) in abs. THF (6 mL) and N-ethyl diisopropylamine (80 μL, 0.49 mmol)and stirred for 16 h at RT. The solution was concentrated to low volumein a vacuum, the residue taken up in ethyl acetate (20 mL) and washedwith saturated NaHCO₃ solution (2×10 mL) and saturated NaCl solution (10mL). The organic phase was dried over Na₂SO₄ and concentrated to lowvolume in a vacuum. The raw product was purified by flash chromatographywith ethyl acetate/methanol (20:1).

Yield: 67 mg (30%)

¹³C-NMR (CDCl₃): 30.4, 31.4, 33.6, 38.0, 59.3, 66.4, 126.4, 126.7,127.0, 127.1, 127.7, 128.2, 137.6, 143.1, 165.4, 168.0, 169.1

Step 2[4-[[4,6-bis(dimethylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

The title compound from step 1 (57 mg, 0.12 mmol) was dissolved in a 2Mdimethylamine solution in THF (2.0 mL, 4 mmol) and stirred in themicrowave for 2 h at 120° C. The reaction solution was concentrated tolow volume in a vacuum, the remaining residue taken up in ethyl acetate(10 mL) and washed with saturated NaHCO₃ solution (2×5 mL) and saturatedNaCl solution (5 mL). The organic phase was dried over Na₂SO₄ andconcentrated to low volume in a vacuum. The raw product was purified byflash chromatography with ethyl acetate/MeOH (20:1).

Melting point: 195-197° C.

Yield: 45 mg (76%)

¹H-NMR (DMSO-d₆): 1.62 (2H, m); 1.98 (6H, s); 2.39 (2H, m); 2.46 (2H,m); 2.91 (12H, s); 3.13 (3H, s); 7.15 (1H, m); 7.22-7.38 (9H, m).

Example 1304-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butan-1-ol(polar diastereomer) Step 1N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-tert-butylsuccinate

The title compound from Example 131 (100 mg, 0.244 mmol) was provided inabs. dichloromethane (5 mL), mixed with trifluoroacetic anhydride (135μL, 0.976 mmol) and stirred for 10 min. Tert-butyl alcohol (2 mL) wasadded to the batch and subsequently stirred for 30 min. The batch wasthen mixed with 10% NaOH and the phases separated. The organic phase waswashed with H₂O (1×10 mL), dried over Na₂SO₄ and concentrated to lowvolume in a vacuum.

Yield: 80 mg (70%)

¹H-NMR (DMSO-d₆): 1.38 (9H, s); 1.53 (2H, m); 1.78 (2H, m); 1.92 (6H,s); 2.37 (3H, m); 2.62 (2H, m); 2.93 (3H, s), 7.11-7.27 (6H, m); 7.36(4H, m).

Step 2

4-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butan-1-01(polar diastereomer)

The title compound from step 1 (836 mg, 1.8 mmol) was dissolved in abs.THF (15 mL). LiAlH₄ (136 mg, 3.6 mmol) was added in argon, boiled for 2h with reflux, cooled to room temperature and stirred overnight. THF (2mL) and H₂O (2 mL) were added to the batch with ice cooling and stirredfor 30 min. The batch was passed through a fritted glass filter withdiatomaceous earth, the diatomaceous earth washed with dichloromethane(50 mL), the organic phases purified and concentrated to low volume in avacuum. The residue was purified by flash chromatography withchloroform/methanol (9:1).

Yield: 405 mg (59%)

¹H-NMR (DMSO-d₆): 1.39 (4H, m); 1.74 (3H, m); 1.96 (6H, s); 2.01 (3H,s); 2.11 (2H, m); 2.30 (3H, m); 3.36 (2H, m); 4.41 (1H, m); 7.18 (2H,m); 7.28 (8H, m).

Example 1313-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-carbamoyl]-propionicacid (polar diastereomer)

Succinic acid anhydride (0.97 g, 9.27 mmol) was heated to 130° C. andmelted. The title compound from Example 9 (1.00 g, 3.24 mmol) was thenadded and the mixture heated further at this temperature for 7 h. Thebatch was purified by flash chromatography with chloroform/methanol(9:1→4:1→1:1→1:2→methanol).

Yield: 1.08 g (81%)

¹H-NMR (DMSO-d₆): 1.55 (2H, m); 1.81 (2H, m); 1.94 (6H, s); 2.37 (4H,m); 2.62 (2H, m); 2.76 (1H, m); 2.94 (3H, s); 7.14 (3H, m); 7.17 (2H,m); 7.26 (1H, m); 7.38 (4H, m).

Example 146[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer) Step 1N-(4-chloro-[1,3,5]triazin-2-yl)-N,N′,N′-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine

A solution of the title compound from Example 9 (462 mg, 1.5 mmol),2,4-dichloro-1,3,5-triazine (225 mg, 1.5 mmol) and diisopropylethylamine (248 μL, 1.5 mmol) in abs. THF (10 mL) was stirred overnightat RT. The solvent was then removed in a vacuum, the remaining residuedissolved in ethyl acetate, washed with saturated NaHCO₃ solution andsaturated NaCl solution, dried over Na₂SO₄ and purified by flashchromatography with ethyl acetate/MeOH (9:1).

Yield: 166 mg (26%)

¹H-NMR (CDCl₃): 1.97 (4H, m); 2.06 (6H, s); 2.47 (4H, bs); 3.01 (2H,breit); 3.34 (3H, s); 7.14-7.40 (10H, m); 8.29 (1H, s).

Step 2[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer)

The title compound of step 1 (166 mg, 0.39 mmol), 4-methoxyphenol (56mg, 0.45 mmol) and sodium hydride (18 mg, 0.45 mmol, 60% dispersion inmineral oil) were stirred in abs. dioxan (10 mL) for 4 h at RT. Thesolvent was then removed in a vacuum, the remaining residue dissolved inethyl acetate, washed with saturated NaHCO₃ solution and saturated NaClsolution, dried over Na₂SO₄ and purified by flash chromatography withethyl acetate/MeOH (4:1).

Yield: 126 mg (63%), porous solid

¹H-NMR (CDCl₃): 1.84 (4H, m); 2.03 (6H, s); 2.60 (4H, breit); 3.23 (3H,s); 3.80 (3H, s); 6.87-7.38 (14H, m); 8.37 (1H, s).

Example 149[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamineStep 1 4-cyano-4-phenyl-heptane dicarboxylic acid-dimethyl ester

Phenyl acetonitrile (11.7 g, 100 mmol) and methylacrylate (47 mL, 500mmol) were provided in tert-butyl alcohol (60 mL) and heated to boiling.The heat source was then removed. Triton B (benzyl trimethyl ammoniumhydroxide, 40% in methanol, 15.2 mL) dissolved in tert-butyl alcohol (23mL) was firstly added slowly in drops and then quickly. After theaddition in drops, the batch was heated to boiling for 4 h. The reactionmixture was cooled to room temperature overnight. For work up the batchwas mixed with toluol (100 mL) and water (70 mL), the organic phaseseparated and washed with water (70 mL) and saturated NaCl solution (50mL). After drying with Na₂SO₄ the solvent was distilled. Purificationoccurred by bulb tube distillation at a temperature of approx. 235° C.The product could be isolated as a colourless, viscous substance.

Yield: 22.5 g (75%)

¹H-NMR (DMSO-d₆): 2.32 (8H, m); 3.51 (6H; s); 7.40 (5H, m).

¹³C-NMR (DMSO-d₆): 22.47; 27.16; 39.28; 44.11; 113.82; 118.55; 120.83;121.78; 129.10; 164.44.

Step 2 5-cyano-2-oxo-5-phenyl-cyclohexane carboxylic acid methyl ester

4-cyano-4-phenyl heptane dicarboxylic acid dimethylester (19.8 g, 68mmol) was dissolved in dry tetrahydrofuran (480 mL). Potassiumtert-butylate (13.2 g, 120 mmol) was then added in portions. During thisaddition the reaction mixture changed colour to orange. The batch wasthen boiled for 5 h with reflux. A brown solution was formed duringboiling. The reaction mixture was cooled to room temperature overnight.2.5N acetic acid (230 mL) was slowly added in drops to the reactionmixture with ice cooling. The batch was then mixed with toluol (100 mL),the organic phase separated and washed with saturated NaHCO₃ solution(3×100 mL), H₂O (3×50 mL) and NaCl solution (1×100 mL). After dryingwith Na₂SO₄ the solvent was distilled off in a vacuum. A yellowish solidremained.

Yield: 16.1 g (92%)

Melting point: 75-77° C.

¹H-NMR (DMSO-d₆): 2.23-2.74 (6H, m); 3.74 (3H; s); 7.35-7.60 (5H, m);12.08 (1H, bs).

¹³C-NMR (DMSO-d₆): 26.95; 30.18; 34.04; 51.90; 94.79; 121.90; 125.46;128.05; 128.85; 138.92; 169.95; 171.09.

Step 3 4-oxo-1-phenyl-cyclohexane carbonitrile

5-cyano-2-oxo-5-phenyl cyclohexane carboxylic acid methyl ester (16.1 g,63 mmol) was dissolved in 10% sulphuric acid (218 mL) and conc. aceticacid (502 mL) and stirred for 21 h at 100° C. For work up the batch wascarefully diluted with water (400 mL) with ice cooling, extracted withethyl acetate (3×100 mL), the organic phase washed thoroughly with water(6×100 mL), saturated NaHCO₃ solution (10×100 mL) and saturated NaClsolution (1×100 mL). After drying with Na₂SO₄ the solvent was distilledoff in a vacuum.

Yield: 8.91 g (72%)

Melting point: 106-107° C.

¹H-NMR (DMSO-d₆): 2.38-2.48 (6H, m); 2.70 (2H; m); 7.36 (1H, m); 7.44(2H, m); 7.62 (2H, m).

¹³C-NMR (DMSO-d₆): 35.31; 38.10; 42.33; 121.73; 125.65; 128.19; 129.02;139.17; 208.79.

Step 4 8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile

The title compound from step 3 (8.91 g, 44.73 mmol) was taken up intoluol (300 mL) and mixed with ethylene glycol (6 mL, 106.8 mmol). Afteradding p-toluol sulphonic acid (0.128 g, 0.745 mmol), the batch washeated to boiling in the water separator for 3.5 h. The course of thereaction was followed by DC. After the reaction batch cooled, the toluolsolution was extracted with water (5×60 mL) and saturated NaCl solution(3×40 mL) and dried over Na₂SO₄. After removal of the solvent in avacuum, the ketone acetal was obtained as yellow solid.

Yield: 11.6 g (100%)

Melting point: 108-110° C.

¹H-NMR (DMSO-d₆): 1.86 (4H, m); 2.01-2.30 (4H; m); 3.92 (4H, s);7.38-7.53 (5H, m).

¹³C-NMR (DMSO-d₆): 32.10; 34.07; 42.49; 63.86: 106.11; 122.14; 125.51;128.16; 129.02; 139.90.

Step 5 8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid

The title compound from step 4 (10.9 g, 46.9 mmol) was dissolved inethylene glycol (92 mL), mixed with NaOH (4.00 g, 100 mmol) and thenheated to boiling with reflux. No further nitrile could be detectedafter 20 h. For work up the batch was mixed with ice (approx. 250 g),coated with ether (90 mL) and acidified by slowly addingsemiconcentrated HCl (118 mL). The aqueous phase was extracted withether (3×70 mL), the combined organic extracts were washed withsaturated NH₄Cl solution (2×70 mL), dried over Na₂SO₄ and concentratedto low volume in a vacuum. By recrystallising the remaining residue fromtoluol the desired carboxylic acid was obtained as crystalline solid.

Yield: 7.42 g (59%)

Melting point: 134-139° C.

¹H-NMR (DMSO-d₆): 1.64 (4H, m); 1.91 (2H; m); 2.41 (2H, m); 3.86 (4H,s); 7.36 (5H, m); 12.52 (1H, bs).

¹³C-NMR (DMSO-d₆): 31.51; 32.05; 49.19; 63.65: 107.23; 125.70; 126.94;128.39; 142.82; 175.53.

Step 6 8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carboxylicacid-benzyl-methylamide

The title compound from step 5 (8.00 g, 30.48 mmol) was dissolved indichloromethane (240 mL) and mixed with 1,3-diisopropyl carbodiimide(4.44 g, 5.44 mL, 35.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate(5.44 g, 35.5 mmol) at 0° C. The reaction mixture was stirred for 5 minwith ice cooling and then N-benzyl methylamine (3.87 g, 4.12 mL, 32.0mmol) was added. The reaction mixture was stirred for 3 d at roomtemperature. For work up the batch was concentrated until dry in avacuum. The residue was purified by flash chromatography withcyclohexane/ethyl acetate (1:1).

Yield: 7.31 g (66%)

¹H-NMR (DMSO-d₆): 1.61 (4H, m); 1.68 (4H, m); 2.35 (3H, m); 3.85 (6H,s); 7.28 (10H, br, m).

Step 7 Benzyl-methyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-amine

The title compound from step 6 (1.20 g, 3.28 mmol) was dissolved in abs.tetrahydrofuran (160 mL), LiAlH₄ (0.25 g, 6.59 mmol) added in argon andstirred for 5 h with reflux. The batch was then cooled to roomtemperature and stirred overnight. The batch was hydrolysed with THF (20mL) and H₂O (20 mL) with ice cooling and subsequently stirred for 30min. The batch was filtered via a fritted glass filter with diatomaceousearth, subsequently washed with THF and dichloromethane (50 mL) andconcentrated to low volume in a vacuum. The residue was purified bymeans of flash chromatography and cyclohexane/ethyl acetate (1:1).

Yield: 0.50 g (43%)

¹H-NMR (DMSO-d₆): 1.35 (2H, m); 1.38 (2H, m); 1.72 (5H, m); 2.20 (2H,d); 2.48 (2H, m); 3.22 (2H, s); 3.84 (4H, m); 7.25 (8H, m), 7.44 (2H d).

Step 8 4-[(benzyl-methyl-amino)-methyl]-4-phenyl-cyclohexanone

The title compound from step 7 (3.40 g, 9.67 mmol) was mixed with 5%sulphuric acid (300 mL) and stirred for 48 h at room temperature. Forwork up the reaction mixture was mixed with ether (100 mL), the phasesseparated and the aqueous phase extracted with ether (2×100 mL). Theaqueous phase was then basified with 5N NaOH and extracted withdichloromethane (3×100 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated until dry in a vacuum.

Yield: 2.74 g (92%)

¹H-NMR (DMSO-d₆): 1.79 (3H, s); 2.07 (2H, m); 2.16 (5H, m); 2.22 (1H,m); 3.26 (2H, s); 7.22 (6H, m); 7.37 (2H, t), 7.55 (2H, d).

Step 94-[(benzyl-methyl-amino)-methyl]-1-methylamino-4-phenyl-cyclohexanecarbonitrile

40% aqueous methylamine solution (5.40 mL, 42.7 mmol) and the titlecompound from step 8 (2.74 g, 8.91 mmol) dissolved in methanol (10 mL)were added to a solution of 4N hydrochloric acid (2.33 mL) and methanol(1.40 mL) cooled to 0° C. The reaction mixture was then mixed withpotassium cyanide (1.40 g, 21.1 mmol) and stirred for 1 d at roomtemperature. For work up the mixture was mixed with water (30 mL) andextracted with ether (3×50 mL). The combined organic phases were driedwith Na₂SO₄, filtered and concentrated to low volume in a vacuum.

Yield: 2.69 g (90%)

¹H-NMR (DMSO-d₆): 1.11 (2H, m); 1.68 (1H, m); 1.72 (2H, m); 1.78 (1H,m); 1.86 (2H, s); 1.92 (2H, m); 2.22 (2H, d). 2.28 (1H, m); 2.38 (2H,m); 2.67 (1H, m); 3.17 (1H, m); 3.29 (2H, m); 7.25 (10H, m).

Step 10{4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl}-methylamine

Phenyl lithium (12.9 mL, 23.2 mmol, 1.8 M in dibutyl ether) was providedin argon, mixed in drops with the title compound from step 9 (2.69 g,7.74 mmol) in THF (15 mL), and the reaction solution was stirred for 1 hwith reflux. The reaction mixture was hydrolysed with saturated NH₄Clsolution (27 mL) with ice bath cooling and the phases separated. Theaqueous phase was extracted with ether (3×50 mL). The combined organicphases were dried over Na₂SO₄, filtered and concentrated until dry in avacuum. The residue was separated by Chromatotron anddichloromethane→dichloromethane/methanol (9:1)→methanol. 1.20 g ofketone were isolated. The desired product was obtained as diastereomermixture and as such was further converted.

Yield: 0.360 g (12%)

¹H-NMR (DMSO-d₆): 1.75 (1H, m); 1.79 (3H, s); 1.92 (1H, m); 2.02 (3H,m); 2.17 (6H, m); 2.46 (1H, m); 2.61 (2H, m); 7.25 (13H, m); 7.54 (2H,m).

Step 11[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine

A solution of the title compound from step 10 (diastereomer mixture)(0.350 g, 0.878 mmol) and formalin (1.23 mL, 37% aqueous solution) inacetonitrile (15 mL) was mixed in portions with sodium cyanoboronhydride (0.250 g, 3.86 mmol) and stirred for 45 min at room temperature.Conc. acetic acid was then added until a neutral reaction occurred andthe mixture was subsequently stirred for 45 min at room temperature. Forwork up the solvent was removed in a vacuum, the residue taken up in 2NNaOH (40 mL) and then extracted with ether (3×40 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to low volumein a vacuum. The remaining residue was purified by Chromatotron and withcyclohexane/ethyl acetate 1:1. Separation of the diastereomers could notbe achieved.

Yield: 70 mg (19%)

¹H-NMR (DMSO-d₆): 1.60 (4H, m); 1.72 (3H, s); 1.82 (6H, s); 2.14 (2H,m); 2.49 (4H, s); 3.19 (2H, s); 6.93 (2H, m); 7.21 (5H, m); 7.40 (8H,m).

Example 153[4-[[4-(benzylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine(polar diastereomer)

The title compound from Example 146, step 1 (100 mg, 0.236 mmol),benzylamine (55 μL, 0.5 mmol) and diisopropyl ethylamine (50 μL, 0.3mmol) dissolved in abs. THF (2.0 mL) were stirred in a closed vessel for5 h at 70° C. The solvent was then removed in a vacuum, the remainingresidue dissolved in dichloromethane, washed with saturated NaHCO₃solution, dried over Na₂SO₄ and purified by flash chromatography withethyl acetate/MeOH (4:1→1:1). The product still contained benzylamine,which was removed in a vacuum at 90° C.

Yield: 83 mg (90%), oil

¹H-NMR (CDCl₃): 1.77 (4H, m); 2.02 (6H, s); 2.37 (2H, m); 2.97 (2H,breit); 3.28 (3H, s); 4.38 (2H, s); 6.01 (1H, s); 7.12-7.40 (15H, m);8.00 (1H, s).

The following compounds were obtained following a specification such asdescribed in Example 153 except that the amines listed in Table 1-10were used.

TABLE 1-10 Ex. Cy (%)/ No. Amine Product MS (m/z) 154 Cyclohexylaminedimethyl-[4-[methyl-(4-piperidin- 71 (471)1-yl-[1,3,5]triazin-2-yl)-amino]- 1,4-diphenyl-cyclohexyl]-amine (polardiastereomer) 155 n-butylamine [4-[(4-butylamino-[1,3,5]triazin- 68(459) 2-yl)-methyl-amino]-1,4-diphenyl- cyclohexyl]-dimethylamine (polardiastereomer) 156 Aniline [4-[(4-anilino-[1,3,5]triazin- 59 (479)2-yl)-methyl-amino]-1,4-diphenyl- cyclohexyl]-dimethyl-amine (polardiastereomer) 157 Isopropyl [4-[[4-(isopropyl-methyl-amino)- 75 (459)methylamine [1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]- dimethylamine (polar diastereomer) 158t-butylamine [4-[[4-(tert-butylamino)- 64 (459)[1,3,5]triazin-2-yl]-methyl- amino]-1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer)

Example 163[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer) Step 18-phenyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid-butyl-methylamide

The title compound from Example 149, step 5 (6.50 g, 24.8 mmol) wasdissolved in dichloromethane (200 mL) and mixed with diisopropylcarbodiimide (3.60 g, 4.41 mL, 28.8 mmol) and 1-hydroxy-1H-benzotriazolehydrate (4.41 g, 28.8 mmol) at 0° C. The reaction mixture was stirredfor 5 h with ice cooling and N-methyl butylamine (2.34 g, 3.08 mL, 26.0mmol) was then added. The reaction mixture was stirred for 2 d at roomtemperature. For work up the batch was concentrated until dry in avacuum. The residue was purified by flash chromatography withcyclohexane/ethyl acetate (2:1).

Yield: 3.50 g (45%)

¹H-NMR (DMSO-d₆): 0.95 (6H, m); 1.39 (2H, s); 1.80 (2H, m); 1.85 (6H,m); 2.24 (2H, m); 2.51 (1H, m); 3.10 (1H, br m).); 3.84 (4H, s); 7.23(3H, m); 7.34 (2H, m).

Step 2 Butyl-methyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-amine

The title compound from step 1 (3.50 g, 10.6 mmol) was dissolved in abs.tetrahydrofuran (400 mL), LiAlH₄ (0.66 g, 17.5 mmol) added in argon andstirred for 5 h with reflux. The batch was then cooled to roomtemperature and stirred overnight. The batch was hydrolysed with THF (20mL) and H₂O (20 mL) with ice cooling and subsequently stirred for 30min. The batch was filtered via a fitted glass filter with diatomaceousearth, rewashed with THF and dichloromethane (50 mL) and concentrated tolow volume in a vacuum. The residue was purified by flash chromatographyand cyclohexane/ethyl acetate (9:1→1:1).

Yield: 2.50 g (76%)

¹H-NMR (DMSO-d₆): 0.77 (3H, t); 1.19 (6H, m); 1.52 (2H, m); 1.77 (2H,m); 1.83 (3H, s); 2.05 (2H, m); 2.18 (2H, m); 2.31 (2H, s); 3.84 (4H, brm); 7.19 (1H, m); 7.33 (4H, m).

Step 3 4-[(butyl-methyl-amino)-methyl]-4-phenyl-cyclohexanone

The title compound from step 2 (2.50 g, 7.8 mmol) was mixed with 5%sulphuric acid (300 mL) and stirred for 48 h at room temperature. Forwork up the reaction mixture was mixed with ether (100 mL), the phasesseparated and the aqueous phase extracted with ether (2×100 mL). Theaqueous phase was basified with 5N NaOH and extracted withdichloromethane (3×10 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated until dry in a vacuum.

Yield: 1.53 g (73%)

¹H-NMR (DMSO-d₆): 0.78 (3H, t); 1.15 (4H, br, m); 1.87 (3H, s); 1.93(2H, m); 2.13 (6H, br m); 2.45 (4H, m); 7.25 (1H, t); 7.37 (2H, t); 7.49(2H, d).

Step 44-[(butyl-methyl-amino)-methyl]-1-methylamino-4-phenyl-cyclohexanecarbonitrile

40% aqueous methylamine solution (3.42 mL, 27 mmol) and the titlecompound from step 3 (1.54 g, 5.60 mmol) dissolved in methanol (5 mL)were added to a solution of 4N hydrochloric acid (1.50 mL) and methanol(0.89 mL) cooled to 0° C. The reaction mixture was then mixed withpotassium cyanide (0.901 g, 13.4 mmol) and stirred for 3 d at roomtemperature. For work up the mixture was mixed with water (50 mL) andextracted with ether (3×100 mL). The combined organic phases were driedover Na₂SO₄, filtered and concentrated to low volume in a vacuum.

Yield: 1.76 g (100%)

¹H-NMR (DMSO-d₆): 0.77 (3H, m); 1.07 (5H, m); 1.68 (3H, m); 1.77 (1H,s); 1.84 (1H, m); 1.92 (2H, m); 2.03 (1H, m); 2.12 (2H, m); 2.21 (2H,m); 2.31 (3H, m); 2.43 (1H, m); 2.63 (1H, m); 7.19 (1H, m); 7.37 (4H,m).

Step 5

{-4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl}-methylamine

Phenyl lithium (9.33 mL, 16.8 mmol, 1.8 M in dibutyl ether) was providedin argon, mixed in drops with the title compound from step 4 (1.76 g,5.61 mmol) in ether (15 mL) and the reaction solution stirred for 1 h at50° C. The reaction mixture was hydrolysed with saturated NH₄Cl solution(100 mL) with ice bath cooling and the phases separated. The aqueousphase was extracted with ether (3×50 mL). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated until dry in a vacuum.The residue was separated by Chromatotron and dichloromethane.

Yield: 0.400 g (20%), non-polar diastereomer

¹H-NMR (DMSO-d₆): 0.71 (3H, t); 1.05 (5H, m); 1.59 (3H, m); 1.76 (6H,s); 2.01 (6H, m); 2.40 (2H, br s); 7.19 (2H, m); 7.34 (6H, m); 7.47 (2H,d).

Yield: 0.170 g (9%), polar diastereomer

¹H-NMR (DMSO-d₆): 0.76 (3H, t); 1.13 (4H, m); 1.37 (2H, m); 1.75 (4H,5); 1.86 (3H, m); 2.06 (6H, m); 2.41 (2H, s); 3.17 (1H, s); 7.13 (2H,m); 7.26 (6H, m); 7.38 (2H, m).

Step 6[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer)

A solution of the title compound from step 6 (non-polar diastereomer)(0.400 g, 1.1 mmol) and formalin (1.54 mL, 37% aqueous solution) inacetonitrile (20 mL) was mixed in portions with sodium cyanoboronhydride (0.313 g, 4.84 mmol) and stirred for 45 min at room temperature.Conc. acetic acid was then added until a neutral reaction occurred andthe mixture subsequently stirred for 45 min at room temperature. Forwork up the solvent was removed in a vacuum, the residue taken up in 2NNaOH (40 mL) and then extracted with ether (3×40 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated to a low volume in avacuum. The residue was purified by Chromatotron anddichloromethane→methanol.

Yield: 220 mg (53%)

¹H-NMR (DMSO-d₆): 0.70 (3H, t); 0.99 (4H, m); 1.42 (2H, m); 1.58 (2H,m); 1.75 (3H, s); 1.86 (6H, s); 1.95 (2H, m); 2.16 (4H, m); 2.32 (2H,m); 7.18 (1H, m); 7.38 (9H, m).

Example 164[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer)

A solution of the title compound from Example 163, step 6 (polardiastereomer) (0.170 g, 0.47 mmol) and formalin (0.66 mL, 37% aqueoussolution) in acetonitrile (8.2 mL) was mixed in portions with sodiumcyanoboron hydride (0.134 g, 2.07 mmol) and stirred for 45 min at roomtemperature. Conc. acetic acid was then added until a neutral reactionoccurred and the mixture stirred for 45 min at room temperature. Forwork up the solvent was removed in a vacuum, the residue taken up in 2NNaOH (40 mL) and then extracted with ether (3×40 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated to a low volume in avacuum. The residue was purified by Chromatotron anddichloromethane→methanol.

Yield: 75 mg (41%)

¹H-NMR (DMSO-d₆): 0.77 (3H, t); 1.18 (5H, m); 1.51 (2H, m); 1.76 (5H,m); 1.94 (6H, s); 2.04 (3H, m); 2.27 (2H, m); 2.40 (2H, s); 7.23 (10H,m).

Nephelometric Solubility Study (Phosphate Buffer pH 7.4):

This method examines the solubility of a substance with fixedconcentrations (1 μM, 3 μM, 10 μM, 30 μM and 100 μM) in 10 mM ofphosphate buffer solution with pH 7.4. A 10 mM solution of thesubstances in DMSO will be initially required, from which 100-fold stocksolutions of the above-mentioned concentration level again in DMSO areproduced, the final DMSO concentration in the test batch amounting to 1%(v/v). The experiment is conducted multiple times for determination.After the DMSO stock solutions have been added to the buffer, the batchis incubated for 2 h at 37° C. before an absorption determination at 620nm occurs. If the absorption of the samples increases above that of thepure buffer/DMSO solution, then this applies as indicator for aprecipitate formation. The lower solubility limit (“lower boundary”) isthe concentration preceding that with the first precipitate formation(e.g. 3 μM if precipitation formation was detected at 10 μM).

Studies on the Efficacy of the Compounds According to the InventionMeasurement of the ORL 1-Bond

The compounds were examined with membranes of recombinant CHO-ORL 1cells in a receptor binding assay with ³H-nociceptin/orphanin FQ. Thistest system was conducted in accordance with the method outlined byArdati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824). Theconcentration of ³H-nociceptin/orphanin FQ amounted to 0.5 nM in thesetests. The binding assays were conducted in each case on 20 μg ofmembrane protein per 200 μl of preparation in 50 mM of HEPES, pH 7.4, 10nM of MgCl₂ and 1 mM of EDTA. The binding to the ORL 1-receptor wasdetermined using 1 mg of WGA-SPA beads (Amersham-Pharmacia, Freiburg) ineach case by incubating the preparation for one hour at RT and thenconducting measurements in the Trilux scintillation counter (Wallac,Finland). The affinity is indicated as nanomolar K_(i) value or in %inhibition at c=1 μM in Table 1.

Measurement of the μ-Bond

The affinity to the human μ-opiate receptor was determined in ahomogeneous preparation in microtiter plates. For this, dilution seriesof the respective compound to be tested were incubated for 90 minutes atroom temperature with a receptor membrane preparation (15-40 μg ofprotein per 250 μl of incubation batch) of CHO-K1 cells, which expressthe human μ-opiate receptor (RB-HOM receptor membrane preparation ofNEN, Zaventem, Belgium), in the presence of 1 nmol/l of the radioactiveligand [³H′-naloxone (NET719, NEN, Zaventem, Belgium) and of 1 mgWGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia,Freiburg, Germany) in a total volume of 250 μl. 50 mmol/l of tris-HClsupplemented by 0.05% by wt. of sodium azide and 0.06% by wt. of bovineserum albumin was used as incubation buffer. 25 μmol/l of naloxone wereadditionally added to determine the non-specific bond. After theninety-minute incubation time had ended, the microtiter plates werecentrifuged for 20 minutes at 1000 g and the radioactivity measured in a(3-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany).The percentage displacement of the radioactive ligand from its bindingto the human μ-opiate receptor was determined with a concentration ofthe test substances of 1 μmol/l and was specified as percentageinhibition (% inhibition) of the specific bond. In some instances,working from the percentage displacement by different concentrations ofthe compounds of the general formula I according to the invention, IC₅₀inhibition concentrations were calculated that effect a 50 percentdisplacement of the radioactive ligand. Ki values for the testsubstances were obtained by conversion using the Cheng-Prusoff equation.In some cases, the determination of the Ki value was omitted and onlythe inhibition with a test concentration of 1 μM was determined.

Measurement of the Kappa-Bond

The determination occurred in a homogeneous batch in microtiter plates.For this, dilution series of the respective substances to be tested wereincubated for 90 minutes at room temperature with a receptor membranepreparation (7 μg of protein per 250 μl of incubation batch) of CHO-K1cells, which express the human κ-opiate receptor, in the presence of 1nmol/l of the radioactive ligand [³H′]-C1-977 and 1 mg WGA-SPA beads(wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg,Germany) in a total volume of 250 μl. 50 mmol/l of tris-HCl supplementedby 0.05% by wt. of sodium azide and 0.06% by wt. of bovine serum albuminwas used as incubation buffer. 100 μmol/l of naloxone were additionallyadded to determine the non-specific bond. After the ninety-minuteincubation time had ended, the microtiter plates were centrifuged for 20minutes at 500 rpm and the radioactivity measured in a β-counter(Microbeta-Trilux 1450, PerkinElmer Wallac, Freiburg, Germany). Thepercentage displacement of the radioactive ligand from its binding tothe human κ-opiate receptor was determined with a concentration of thetest substances of 1 μmol/l and was specified as percentage inhibition(% inhibition) of the specific bond. Working from the percentagedisplacement by different concentrations of the compounds to be tested,IC₅₀ inhibition concentrations can be calculated that effect a 50percent displacement of the radioactive ligand. Ki values for the testsubstances can be calculated by conversion using the Cheng-Prusoffequation.

The results are collated in the following table:

% Inhibition Ki (ORL1) % Inhibition Ki (μ) Mean Ex. (ORL1) [1 μM] Mean[μM] (μ) [1 μM] [μM] 1 26 n.d. 46 n.d. 2 9 n.d. 22 n.d. 3 81 n.d. 0 n.d.4 33 0.94 38 n.d. 5 37 0.635 82 0.0705 6 51 0.18 83 0.049 7 34 0.99 48.1.16 8 14 n.d. 30 n.d. 9 80 0.01775 49 0.64 10 18 n.d. 34 n.d. 11 870.006 59 0.6 12 53 0.365 86 0.0805 13 36 1.31 66 0.155 14 17 n.d. 67n.d. 15 83 n.d. 98 n.d. 16 18 n.d. 65 n.d. 17 17 1.17 61 0.14 18 950.0027 100 0.00125 19 94 0.017 96 0.0475 20 92 0.011 101 0.0011 21 430.49 57 0.78333 22 43 n.d. 92 n.d. 23 13 n.d. 15 n.d. 24 82 0.063 970.01425 25 60 0.19 91 0.0154 26 76 n.d. 69 n.d. 27 95 0.0049 98 0.0080528 30 1.01 36 0.895 29 70 0.09 98 0.0015 30 93 0.0016 99.5 0.0022 31 600.0955 90 0.022 32 65 0.051 81 0.052 33 9 3.955 42 1.11 34 27 1.89 810.215 35 29 0.99333 n.d. 0.41 36 30 n.d. n.d. n.d. 37 66 0.1025 n.d.2.455 38 35 n.d. 29 n.d. 39 73 0.0535 93 0.555 40 84 0.0255 46 0.445 4119 n.d. 42 4.11 42 28 1.395 101 0.0018 43 35 0.755 58 0.1305 44 680.0775 96 0.01335 45 72 0.0485 99 0.00124 46 49 0.72 84 0.188 47 391.605 65 0.755 48 22 1.25 48 0.9 49 97 0.00155 93 0.0615 50 58 0.1045 690.12 51 91 0.00128 90 0.044 52 87 0.01 93 0.018 53 61 n.d. 18 n.d. 54 36n.d. 61 n.d. 56 22 n.d. 56 n.d. 57 43 n.d. 80 n.d. 58 52 0.425 71 0.11559 69 0.175 80 0.034 60 47 0.53 77 0.107 61 56 0.375 84 0.032 62 490.0895 85 0.0475 63 60 0.087 91 0.0066 64 83 0.0345 96 0.0053 65 490.435 74 0.0925 66 35 4.01 18 10.23 67 31 n.d. 38 5.205 68 15 n.d. 43n.d. 69 50 0.20667 40 0.65 70 28 n.d. 77 n.d. 71 38 0.36 55 1.19 72 580.115 40 1.695 73 45 0.165 84 0.027 74 67 0.057 52 0.66 75 24 2.955 340.67 76 55 0.295 83 0.18 77 98 0.00071 100 0.0004 78 39 0.73 67 0.385 7996 n.d. 95 n.d. 80 91 n.d. 99 n.d. 81 82 n.d. 91 n.d. 82 53 n.d. 78 n.d.83 47 n.d. 82 n.d. 84 72 n.d. 97 n.d. 85 99 0.00081 n.d. 0.115 86 35n.d. n.d. n.d. 87 53 n.d. n.d. n.d. 88 54 n.d. n.d. n.d. 89 24 1.075n.d. 0.325 90 44 0.525 n.d. 1.055 91 98 0.00535 n.d. 0.74 92 97 0.015n.d. 0.00635 93 84 0.235 n.d. 0.045 94 68 n.d. 83 n.d. 95 32 n.d. 49n.d. 96 64 0.108 62 0.235 97 18 n.d. 32 n.d. 98 91 n.d. 101 n.d. 99 97.50.00054 100 0.0012 100 85 0.21 97 2.4 101 93 0.00245 79 0.063 102 18n.d. 37 3.73 103 25 n.d. 64 n.d. 104 67 0.033 93 0.01 105 93 0.00065 1010.0012 106 87 0.02 98 0.435 107 19 1.485 38 1.995 108 53 n.d. 89 n.d.109 60 n.d. 43 n.d. 110 38 0.62 78 0.155 111 27 1.055 60 0.42 112 47n.d. n.d. n.d. 113 48 n.d. n.d. n.d. 114 91 0.01385 n.d. 0.13 115 241.165 n.d. 1.66667 116 85 0.021 n.d. 0.014 117 76 0.00013 n.d. 0.00035118 52 n.d. n.d. n.d. 119 89 0.00143 n.d. 0.039 120 36 0.465 n.d. 2.9121 70 0.23 n.d. 1.425 122 83 0.0074 n.d. 0.17667 123 65 n.d. n.d. 2.595124 23 n.d. n.d. 0.735 125 35 2.05 n.d. 0.255 126 23 n.d. n.d. n.d. 12718 n.d. 28 n.d. 128 15 0.93 46 0.255 129 67 n.d. 33 n.d. 130 88 0.018 620.415 131 37 n.d. 22 9.02 132 52 0.19 21 1.58 133 34 n.d. 37 n.d.—notdetermined.

Examination of the Pharmacological Properties of the Exemplary Compounds

Chung Model: Mononeuropathic Pain after Spinal Nerve Ligature

Animals: Male Sprague Dawley rats (140-160 g) from a commercial breeder(Janvier, Genest St: Isle, France) were held under a 12:12 h light-darkrhythm. The animals were kept with a free choice of feed and tap water.A break of one week was adhered to between delivery of the animals andthe operation. The animals were tested multiple times after operationover a period of 4-5 weeks, in which case a wash out time of at leastone week was adhered to.

Model description: Under pentobarbital narcosis (Narcoren®, 60 mg/kgi.p., Merial GmbH, Hallbergmoos, Germany), the left L5, L6 spinal nerveswere exposed by removing a piece of paravertebral muscle and a portionof the left spinal process of the L5 lumbar vertebral body. The spinalnerves L5 and L6 were carefully isolated and bound with a firm ligature(NC silk black, USP 5/0, metric 1, Braun Melsungen AG, Melsungen,Germany) (Kim and Chung 1992). After ligature the muscle and adjacenttissue were sutured and the wound closed by metal clamps.

After a one-week recovery time the animals are placed in cages with awire base for measurement of the mechanical allodynia. The pull-awaythreshold was determined at the ipsi- and/or contralateral rear paw bymeans of an electronic von Frey filament (Somedic AB, Malmö, Sweden).The median of five stimulations gave a data point. The animals weretested 30 min before application and at various times after applicationof test substance or vehicle solution. The data were determined as %maximum possible effect (% MPE) from the pre-testing of individualanimals (=0% MPE) and the test values of an independent sham controlgroup (=100% MPE). Alternatively the pull-away thresholds were shown ingram.

Statistical evaluation: ED₅₀ values and 95% confidence intervals weredetermined by means of semi-logarithmic regression analysis at the timeof maximum effect. The data were analysed by means of a varianceanalysis with repeated measurements as well as a Bonferroni post hocanalysis procedure. The group size usually amounted to n=10.

REFERENCES

-   Kim, S. H. and Chung, J. M.: An experimental model for peripheral    neuropathy produced by segmental spinal nerve ligature in the rat,    Pain, 50 (1992) 355-363.

The results are collated in the following table (Chung model):

Ex. No. MPE (%), (Dose in μg/kg, rat, i.v.) 11 25 (100) 51 29 (100) 3016 (100)

The compounds according to the invention of type E where W=—NHMe or—NMe₂ (Ex. 9, 11 and 13) were compared with corresponding compounds oftype E where W=—OH(C-1 and C-2):

(E)

Ki Ki Ki (ORL1) (μ) (kappa) Ki (μ)/ Ki (kappa)/ Mean Mean Mean Ex. W QR₃ Ki (ORL1) Ki (ORL1) [μM] [μM] [μM]  9

36 65 0.018 0.640 1.170 11

100 193 0.006 0.600 1.160 C-1:

0.7 0.8 2.92 1.89 2.24 13

0.1 2.9 1.310 0.155 3.745 C-2:

0.003 1.46 1.000 0.003 1.460

As the above comparison data show, the compounds according to theinvention (W=—NHMe or —NMe₂) have a higher selectivity with respect tothe kappa-opioid receptor (defined as 1/[K_(i(ORL1))/K_(i(kappa))])compared to the structurally similar substances (W=OH). Moreover, with afavourable ORL 1/μ affinity ratio, the substances according to theinvention also have a higher selectivity with respect to the μ-opioidreceptor (defined as 1/[K_(i(ORL1))/K_(i(μ))]).

The compounds according to the invention of type 1 where n=0, X=—NMe andQ=phenyl (Ex. 27, 30, 31, 32, 49, 85 and 92) were compared to compoundsof type F (C-3 to C-5) where Z=NMe or NCOR, R₅, R₆=H, W=NH, A₁₋₄=CH andR₁ to R₃, Y₁ to Y₄ and Y₁′ to Y₄′ corresponding to (1)

(1)

(F)

Nephelometry (lower boundary) Ex. R_(B) Z Diastereomer μM  1 Me NA polar100 49

not applicable polar 100 85

not applicable polar 100 C-3: not applicable NMe polar 3 92

not applicable polar 100 27

not applicable polar 100 c-4: not applicable

polar 12 30

not applicable polar 100 C-5: not applicable

non-polar 12 31

not applicable non-polar 100 32

not applicable polar 100

As the above comparison shows, the compounds according to the inventionfrom Examples 27, 30, 31, 32, 49, 85 and 92 have a better solubility inaqueous media compared to structurally similar compounds (C-3 to C-5),which in particular should be associated with advantages with respect tothe resorption properties and/or bioavailability.

1. A compound of the formula (1):

wherein Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ are respectively selectedindependently of one another from the group consisting of —H, —F, —Cl,—Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀,—C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀,—OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; or Y₁ andY₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ jointly stand for ═O; Qstands for —R₀, —C(═O)—R₀, —C(═O)OR₀, —C(═O)NHR₀, —C(═O)N(R₀)₂ or—C(═NH)—R₀, R₀ respectively independently stands for —C₁₋₈-aliphatic,—C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,—C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl,—C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic,—C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; R₁ and R₂,independently of one another, stand for —H or —R₀; or R₁ and R₂ jointlyform a ring and stand for —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₄CH₂CH₂— or—(CH₂)₃₋₆—; on condition that R₁ and R₂ do not both simultaneously standfor —H; R₃ stands for —R₀; R₄ respectively independently stands for —H,—R₀ or —C(═O)R₀; n stands for a whole number from 0 to 12; X stands for—O—, —S— or —NR_(A)—; R_(A) stands for —H, —R₀, —S(═O)₀₋₂R₀, —C(═O)R₀,—C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀ or —C(═O)N(R₀)₂; R_(B) stands for —H,—R₀, —C(═O)H, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)N(R₀)₂, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂—OR₀, —S(═O)₁₋₂—NH₂, —S(═O)₁₋₂—NHR₀or —S(═O)₁₋₂—N(R₀)₂; or R_(A) and R_(B) jointly form a ring and standfor —(CH₂)₂₋₅—, —CH₂CH₂OCH₂CH₂— or —CH₂CH₂NR₄CH₂CH₂—; on condition thatwhen X stands for —O— and at the same time n stands for 0, R_(B) doesnot stand for —H; wherein “aliphatic” respectively is a branched orunbranched, saturated or a mono- or polyunsaturated, unsubstituted ormono- or polysubstituted, aliphatic hydrocarbon residue;“cycloaliphatic” respectively is a saturated or a mono- orpolyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic,mono- or multicyclic hydrocarbon residue; wherein with respect to“aliphatic” and “cycloaliphatic”, “mono- or polysubstituted” means themono- or polysubstitution of one or more hydrogen atoms by substituentsselected independently of one another from the group consisting of —F,—Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH,—C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H,—OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H,—S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻,—NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)—NHR₀, —NH—C(═O)N(R₀)₂,—Si(R₀)₃ and —PO(OR₀)₂; “aryl”, respectively independently, stands for acarbocyclic ring system with at least one aromatic ring, but withoutheteroatoms in this ring, wherein, optionally, the aryl residues can becondensed with further saturated, (partially) unsaturated or aromaticring systems, and each aryl residue can be present in unsubstituted ormono- or polysubstituted form, wherein the aryl substituents can be thesame or different and in any desired and possible position of the aryl;“heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromatic residue,which contains 1, 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms, thesame or different, are nitrogen, oxygen or sulphur, and the heterocyclecan be unsubstituted or mono- or polysubstituted; wherein in the case ofthe substitution on the heterocycle the substituents can be the same ordifferent and can be in any desired and possible position of theheteroaryl; and wherein the heterocycle can also be part of a bi- orpolycyclic system; wherein with respect to “aryl” and “heteroaryl”,“mono- or polysubstituted” means the mono- or polysubstitution of one ormore hydrogen atoms of the ring system by substituents selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀,—C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,—C(═O)—N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,—OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,—S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,—NHC(═O)OR₀, —NH—C(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃ or—PO(OR₀)₂; wherein any N-ring atoms present can be respectivelyoxidised; said compound being in the form of a single stereoisomer ormixture thereof, the free compound and/or a physiologically compatiblesalt thereof; except for 4-(dimethylamino)-1-methyl-4-p-tolyl cyclohexylacetate.
 2. Compound according to claim 1, wherein n=0 and X stands for—NR₄—.
 3. Compound according to claim 1, which has the formula (2):

wherein (hetero)aryl stands for heteroaryl or aryl, respectivelyunsubstituted or mono- or polysubstituted, wherein the substituents areselected independently of one another from the group consisting of —F,—Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH,—C(═O)OR₀, —C(═O)NH₂, —C(═O)NH—R₀, —C(═O)—N(R₀)₂, —OH, —O(CH₂)₁₋₂O—,—OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH,—SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃,—N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)—OR₀, —NH—C(═O)NH₂, —NHC(═O)NHR₀ and—NHC(═O)N(R₀)₂.
 4. Compound according to claim 3, which has the formula(2.2):

wherein R_(C) stands for —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —OH or—OCH₃.
 5. Compound according to claim 1, wherein Q stands for—C₁₋₈-aliphatic, -aryl, —C₁₋₈-aliphatic-aryl, -heteroaryl,—C(═O)-heteroaryl or —C(═NH)-heteroaryl; R₁ stands for —CH₃; R₂ standsfor —H or —CH₃; or R₁ and R₂ jointly form a ring and stand for—(CH₂)₃₋₄—; X stands for —O— or —NR_(A)—; R_(A) stands for —H or—C₁₋₈-aliphatic; R_(B) stands for —H, —C₁₋₈-aliphatic,—C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C(═O)—C₁₋₈-aliphatic,—C(═O)—C₁₋₈-aliphatic-aryl, —C(═O)—C₁₋₈-aliphatic-heteroaryl,—C(═O)—C₃₋₈-cycloaliphatic-aryl, —C(═O)—C₃₋₈-cycloaliphatic-heteroaryl,—C(═O)NH—C₁₋₈-aliphatic, —S(═O)₁₋₂—C₁₋₈-aliphatic, —S(═O)₁₋₂-aryl,—S(═O)₁₋₂-heteroaryl, —S(═O)₁₋₂—C₁₋₈-aliphatic-aryl,—S(═O)₁₋₂—C₁₋₈-aliphatic-heteroaryl, —S(═O)₁₋₂—C₃₋₈-cycloaliphatic-arylor —S(═O)₁₋₂—C₃₋₈-cycloaliphatic-heteroaryl; or R_(A) and R_(B) jointlyform a ring and stand for —(CH₂)₃₋₄—; on condition that when X standsfor —O— and at the same time n stands for 0, R_(B) does not stand for—H; R_(C) stands for —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —OH or—OCH₃; and n stands for 0, 1, 2, 3 or 4; wherein aliphatic, aryl andheteroaryl are respectively unsubstituted or mono- or polysubstituted.6. Compound according to claim 5, wherein Q stands for —C₁₋₈-alkyl,-phenyl, —C₁₋₈-alkyl-phenyl, -indolyl, —C(═O)-indolyl or—C(═NH)-indolyl; R₁ stands for —CH₃; R₂ stands for —H or —CH₃; or R₁ andR₂ jointly form a ring and stand for —(CH₂)₃₋₄—; X stands for —O— or—NR_(A)—; R_(A) stands for —H or —C₁₋₈-alkyl; R_(B) stands for —H,—C₁₋₈-alkyl, —C₁₋₈-alkyl-phenyl, —C₁₋₈-alkyl-indolyl, —C(═O)—C₁₋₈-alkyl,—C(═O)—C₁₋₈-alkyl-aryl, —C(═O)—C₁₋₈-alkyl-heteroaryl, —C(═O)—cyclopropyl-aryl, —C(═O)-cyclopropyl-heteroaryl, —C(═O)NH—C₁₋₈-alkyl,—S(═O)₂—C₁₋₈-alkyl, —S(═O)₂—C₁₋₈-alkyl-aryl,—S(═O)₂—C₁₋₈-alkyl-heteroaryl, —S(═O)₂-cyclopropyl-aryl,—S(═C)₂-cyclopropyl-heteroaryl —S(═O)₂-phenyl; or R_(A) and R_(B)jointly form a ring and stand for —(CH₂)₃₋₄—; on condition that when Xstands for —O— and at the same time n stands for 0, R_(B) does not standfor —H; R_(C) stands for —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —OH or—OCH₃; and n stands for 0, 1, 2, 3 or 4; wherein aliphatic, aryl andheteroaryl are respectively unsubstituted or mono- or polysubstituted.7. Compound according to claim 1, which is selected from the groupconsisting of:1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diaminebis(2-hydroxypropane-1,2,3-tricarboxylate);4-(dimethylamino)-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)(1-methyl-1H-indol-2-yl)methanone;1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diaminebis(2-hydroxypropane-1,2,3-tricarboxylate);1,4-bis(dimethylamino)-4-phenylcyclohexyl)(1-methyl-1H-indol-2-yl)methanone;4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine;4-(dimethylamino)-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)(1-methyl-1H-indol-2-yl)methanone;N¹,N1,N4-trimethyl-1,4-diphenylcyclohexane-1,4-diamine;N¹,N1,N4,N4-tetramethyl-1,4-diphenylcyclohexane-1,4-diamine;1-benzyl-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine;4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine2-hydroxypropane-1,2,3-tricarboxylate;4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine;4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine2-hydroxypropane-1,2,3-tricarboxylate;N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)acetamide2-hydroxypropane-1,2,3-tricarboxylate;4-chloro-N-((−4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzol-sulphonamide2-hydroxypropane-1,2,3-tricarboxylate;N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzol-sulphonamide2-hydroxypropane-1,2,3-tricarboxylate;N-((−4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol;N(4-((dimethylamino)methyl)-N,N-dimethyl-1,4-diphenylcyclohexanamine;4-benzyl-4-((dimethylamino)methyl)-N,N-dimethyl-1-phenylcyclohexanamine;4-(((1H-indol-2-yl)methylamino)methyl)-N,N,4-trimethyl-1-phenylcyclohexanamine;N1,N1,N4,N4-tetramethyl-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexane-1,4-diamine;N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-methylcinnamamide;andN-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-methylacetamide;[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamine;(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethylamine(non-polar diastereomer);(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-acetamide(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulphonamide(polar diastereomer);(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide(polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-acetamide (polardiastereomer);3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea(non-polar diastereomer);3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea(polar diastereomer);1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea(non-polar diastereomer);1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea (polardiastereomer);(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine(polar diastereomer);(1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethylamine(polar diastereomer);[4-(dimethylamino)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-dimethylamino-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethylamine (polardiastereomer);dimethyl-(4-methylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine(non-polar diastereomer);dimethyl-(4-methylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine(polar diastereomer);[4-(dimethylamino)-4-phenyl-1-thiophen-2-yl-cyclohexyl]-dimethylamine(polar diastereomer);(4-dimethylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-dimethylamine(non-polar diastereomer);(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide(polar diastereomer);(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide(non-polar diastereomer);(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-2-phenyl-ethylenesulphonamide (non-polar diastereomer);(E)-N-[[4-dimethylamino-4-(3-fluorophenyl)-1-methyl-cyclohexyl]-methyl]-2-phenyl-ethylenesulphonamide (polar diastereomer);(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethylamine (non-polardiastereomer); (1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethylamine(polar diastereomer);[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (polardiastereomer);[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (polardiastereomer);N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-acetamide(polar diastereomer);dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-aminedihydrochloride (polar diastereomer);dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-amine;[4-(acetidin-1-yl)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulphonamide(non-polar diastereomer);(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethylamine (non-polardiastereomer);(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethylamine (polardiastereomer);[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methylamine(non-polar diastereomer);[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methylamine(polar diastereomer);[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide(non-polar diastereomer);(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide(polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methylamino]-acetic acid(polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid(non-polar diastereomer);[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine(non-polar diastereomer);dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine(polar diastereomer);[4-(dimethylamino)-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethylamine(polar diastereomer);[4-dimethylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(dimethylamino)-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);[3-[[[4-(dimethylamino)-1-methyl-4-phenyl-cyclohexyl]-methyl-methyl-amino]-methyl]-1H-indol-1-yl]-methanol(polar diastereomer);(E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide(polar diastereomer);[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methylamine(polar diastereomer);[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methylamine(non-polar diastereomer);benzyl-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-amine;2-hydroxy-propane-1,2,3-tricarboxylic acid;dimethyl-[4-[methyl-(pyridin-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine(polar diastereomer);[4-[[4,6-bis(methylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N-methyl-pyridin-3-carboxylicacid amide (non-polar diastereomer);dimethyl-[4-[methyl-(pyridin-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine(non-polar diastereomer);[4-[[4,6-bis(methylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazol-3-carboxylicacid amide (polar diastereomer);N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazol-3-carboxylicacid amide (non-polar diastereomer);[4-(dimethylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(polar diastereomer);4-(acetidin-1-yl)-1-(3-fluorophenyl)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine(non-polar diastereomer);4-(acetidin-1-yl)-1-(3-fluorophenyl)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine(polar diastereomer);[4-dimethylamino-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide(polar diastereomer);[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazol-3-yl)-methyl]-amine(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazol-3-yl)-methyl]-amine(non-polar diastereomer);[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methylamine(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methylamine(non-polar diastereomer);[1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine(non-polar diastereomer);[1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine(polar diastereomer);[1-(3-fluorophenyl)-4-methylamino-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine;dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-piperidin-1-yl-cyclohexyl]-amine(non-polar diastereomer);[1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-piperidin-1-yl-cyclohexyl]-dimethylamine(polar diastereomer);[4-(dimethylamino)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide(non-polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-fluorophenyl)-methyl]-methylamine(non-polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-fluorophenyl)-methyl]-methylamine(polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol(polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl-acetamide(polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-acetamide(polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl-acetamide(non-polar diastereomer);2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-acetamide(non-polar diastereomer);[4-dimethylamino-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine(non-polar diastereomer);2-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol(non-polar diastereomer);[4-[[4,6-bis(dimethylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);dimethyl-[4-[methyl-(4-methylamino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine(polar diastereomer);4-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butan-1-ol(polar diastereomer);3-[[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-methyl-carbamoyl]-propionicacid (polar diastereomer);[4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethylamine(polar diastereomer);[1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-piperidin-1-yl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(acetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-fluorophenyl)-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(acetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-fluorophenyl)-cyclohexyl]-dimethylamine(polar diastereomer);[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholin-4-yl-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethylamine(polar diastereomer);dimethyl-[4-methylamino-4-(3-methyl-1H-indol-2-yl)-1-thiophen-2-yl-cyclohexyl]-amine(polar diastereomer);[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholin-4-yl-1-phenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[(4-anilino-6-methylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[[4-(isopropyl-methyl-amino)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[(4-anilino-6-methylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[[4-(benzylamino)-6-methylamino-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[(4-butylamino-6-methylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);(1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-methylamine (polardiastereomer); (1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-methylamine(non-polar diastereomer);[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine;[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-thiophen-2-yl-cyclohexyl]-methylamine(non-polar diastereomer);(1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-dimethylamine (polardiastereomer); (1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-dimethylamine(non-polar diastereomer);[4-[[4-(benzylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);dimethyl-[4-[methyl-(4-piperidin-1-yl-[1,3,5]triazin-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine(polar diastereomer);[4-[(4-butylamino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[(4-anilino-[1,3,5]triazin-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[[4-(isopropyl-methyl-amino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-[[4-(tert-butylamino)-[1,3,5]triazin-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);[4-(cyclohexyl-methylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-(cyclopentylamino)-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-anilino-1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethylamine;[1-(3-fluorophenyl)-4-(3-methyl-1H-indol-2-yl)-4-(pyridin-4-ylamino)-cyclohexyl]-dimethylamine;[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine(non-polar diastereomer);[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethylamine(polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-cyclohexanecarboxylic acid amide (polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-tetrahydro-pyran-4-carboxylicacid amide (polar diastereomer);cyclohexyl-methyl-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methylamine(polar diastereomer);(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-(tetrahydro-pyran-4-yl-methyl)-amine(polar diastereomer);N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N,1-dimethyl-piperidin-4-carboxylicacid amide (polar diastereomer); and(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-piperidin-4-yl)-methyl]-amine(polar diastereomer); and physiologically compatible salts thereof.
 8. Apharmaceutical composition comprising at least one compound according toclaim 1, said compound being in the form of a single stereoisomer ormixture thereof, the free compound and/or a physiologically compatiblesalt thereof, and optionally suitable additives and/or adjuvants and/orfurther active substances.
 9. A method of treating pain in a patient inneed of such treatment, said method comprising administering to saidpatient an effective amount therefor of a compound according to claim 1,said compound being in the form of a single stereoisomer or mixturethereof, the free compound and/or a physiologically compatible saltthereof.
 10. A method of treating a condition in a patient in need ofsuch treatment, said method comprising administering to said patient aneffective amount therefor of a compound according to claim 1, saidcompound being in the form of a single stereoisomer or mixture thereof,the free compound and/or a physiologically compatible salt and/orsolvate thereof, wherein said condition is selected from the groupconsisting of anxiety conditions, stress and stress-related syndromes,depressive illnesses, epilepsy, Alzheimer's disease, senile dementia,general cognitive dysfunctions, learning and memory disabilities (asnootropic), withdrawal symptoms, alcohol and/or drug and/or medicationmisuse and/or dependence, sexual dysfunctions, cardiovascular diseases,hypotension, hypertension, tinitus, pruritus, migraine, hearingimpairment, deficient intestinal motility, eating disorders, anorexia,bulimia, mobility disorders, diarrhoea, cachexia, urinary incontinence,or as muscle relaxant, anticonvulsive or anaesthetic, or wherein saidadministering is for coadministration in the treatment with an opioidanalgesic or with an anaesthetic, for diuresis or anti-natriuresis,anxiolysis, for modulating movement activity, for modulatingneurotransmitter release and for treating neuro-degenerative diseasesassociated therewith, for treating withdrawal symptoms and/or forreducing the addiction potential of opioids.